578 results on '"Shaw, Andrey S"'
Search Results
202. The Conserved Box 1 Motif of Cytokine Receptors Is Required for Association with JAK Kinases
- Author
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Tanner, J.William, primary, Chen, Wen, additional, Young, Robert L., additional, Longmore, Gregory D., additional, and Shaw, Andrey S., additional
- Published
- 1995
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203. Interactions of TCR tyrosine based activation motifs with tyrosine kinases
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Shaw, Andrey S., primary, Timson, Lisa K., additional, and Zhu, Gauen Yuexin, additional
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- 1995
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204. p62 Association with RNA Is Regulated by Tyrosine Phosphorylation
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Wang, Lawrence L., primary, Richard, Stéphane, additional, and Shaw, Andrey S., additional
- Published
- 1995
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205. Immunoglobulin-like transcript receptors on human dermal CD14+ dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming.
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Banchereau, Jacques, Zurawski, Sandra, Thompson-Snipes, LuAnn, Blanck, Jean-Philippe, Clayton, Sandra, Munk, Adiel, Yanying Cao, Zhiqing Wang, Sunaina Khandelwal, Jiancheng Hu, McCoy IV, William H., Palucka, Karolina A., Yoram Reiter, Fremont, Daved H., Zurawski, Gerard, Colonna, Marco, Shaw, Andrey S., and Klechevsky, Eynav
- Subjects
IMMUNOGLOBULINS ,CYTOTOXIC T cells ,DENDRITIC cells ,CYTOKINES ,CELL receptors - Abstract
Human Langerhans cells (LCs) are highly efficient at priming cytolytic CD8
+ T cells compared with dermal CD14+ dendritic cells (DCs). Here we show that dermal CD141 DCs instead prime a fraction of naïve CD8+ I cells into cells sharing the properties of type 2 cytokinesecreting CD8+ T cells (1C2). Differential expression of the CDSantagonist receptors on dermal CD14+ DCs, the Ig-like transcript (ILl) inhibitory receptors, explains the difference between the two types of DCs. Inhibition of CD8 function on LC5 inhibited cytotoxic T lymphocytes (CRs) and enhanced 1C2 generation. In addition, blocking ILT2 or ILT4 on dermal CD14+ DCs enhanced the generation of CTLs and inhibited TC2 cytokine production. Lastly, addition of soluble ILT2 and 1L14 receptors inhibited CR priming by LCs. Thus, ILT receptor expression explains the polarization of CD8+ 1-cell responses by LCs vs. dermal CD14+ DCs. [ABSTRACT FROM AUTHOR]- Published
- 2012
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206. Mapping of Sites on the Src Family Protein Tyrosine Kinases p55blk, p59fyn, and p56lynWhich Interact with the Effector Molecules Phospholipase C-γ2, Microtubule-Associated Protein Kinase, GTPase-Activating Protein, and Phosphatidylinositol 3-Kinase
- Author
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Pleiman, Christopher M., primary, Clark, Marcus R., additional, Gauen, Lisa K. Timson, additional, Winitz, Sim, additional, Coggeshall, K. Mark, additional, Johnson, Gary L., additional, Shaw, Andrey S., additional, and Cambier, John C., additional
- Published
- 1993
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207. A dual function of NKG2 D ligands in NK-cell activation.
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Cheney, Elizabeth E., Wise, Erica L., Bui, Jack D., Schreiber, Robert D., Carayannopoulos, Leonidas N., Spitzer, Dirk, Zafirova, Biljana, Polic, Bojan, Shaw, Andrey S., and Markiewicz, Mary A.
- Abstract
NK-cell killing requires both the expression of activating receptor ligands and low MHC class I expression by target cells. Here we demonstrate that the expression of any of the murine ligands for the NK-cell activating receptor NKG2 D results in a concomitant reduction in MHC class I expression. We show this both in tumor cell lines and in vivo. NK-cell lysis is enhanced by the decrease in MHC class I expression, suggesting the change is biologically relevant. These results demonstrate that NKG2 D ligand expression on target cells not only allows for activating receptor recognition, but also actively reduces expression of the inhibitory ligand, MHC class I, leading to enhanced recognition and killing by NK cells. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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208. Podocytes use FcRn to clear lgG from the glomerular basement membrane.
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Akilesh, Shreeram, Huber, Tobias B., Hui Wu, Wang, Gary, Hartleben, Björn, Kopp, Jeffrey B., Miner, Jeffrey H., Roopenian, Deny C., Unanue, Emil R., and Shaw, Andrey S.
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GLOMERULAR filtration rate ,KIDNEY function tests ,KIDNEY glomerulus ,BIOLOGICAL membranes ,URINARY organs ,PLASMA cells - Abstract
The glomerular filtration barrier prevents large serum proteins from being lost into the urine. It is not known, however, why the filter does not routinely dog with large proteins that enter the glomerular basement membrane (GBM). Here, we provide evidence that an active transport mechanism exists to remove immunoglobulins that accumulate at the filtration barrier. We found that FcRn, an lgG and albumin transport receptor, is expressed in podocytes and functions to internalize lgG from the GBM. Mice lacking FcRn accumulated lgG in the GBM as they aged, and tracer studies showed delayed clearance of lgG from the kidneys of FcRn-deficient mice. Supporting a role for this pathway in disease, saturating the clearance mechanism potentiated the pathogenicity of nephrotoxic sera. These studies support the idea that podocytes play an active role in removing proteins from the GBM and suggest that genetic or acquired impairment of the clearance machinery is likely to be a common mechanism promoting glomerular diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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209. Glomerular expression of transforming growth factor–β (TGF-β) isoforms in mice lacking CD2-associated protein.
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Woroniecki, Robert P., Schiffer, Mario, Shaw, Andrey S., Kaskel, Frederick J., and Bottinger, Erwin P.
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TRANSFORMING growth factors-beta ,KIDNEY glomerulus ,CHRONIC kidney failure ,PROTEINURIA ,MICRODISSECTION ,MESSENGER RNA - Abstract
Mice lacking CD2-associated protein (CD2AP−/−) develop glomerular lesions resembling human focal segmental glomerulosclerosis (FSGS) between 3–4 weeks of age and die approximately 2 weeks later from massive proteinuria and renal failure. The mechanisms involved in the glomerular injury in this model are unclear. In this study, we used laser capture microdissection (LCM) and real-time PCR, and examined expression of TGF-ß isoforms in CD2AP−/− mice at the level of isolated glomeruli. Total RNA yield from cryosections of 30 glomeruli was 10.71 ng (SD, 5.45) in CD2AP+/+ group ( n =7), and 4.20 ng (SD, 2.04) in CD2AP−/− group ( n =8), p =0.008. Expression of TGF-ß1 mRNA was increased 1.5-fold in the whole kidney ( p =0.030), and twofold in isolated CD2AP−/− glomeruli ( p =0.026). Whole kidney mRNA of TGF-ß receptor I (RI) and II (RII) was not different in CD2AP−/− and CD2AP+/+ animals, but it was increased in CD2AP−/− glomerular samples by 4.38-fold ( p =0.001) and 11.37-fold ( p =0.0163), respectively. By using LCM we confirmed increased glomerular expression levels of TGF-ß isoforms previously described by our group in glomeruli isolated by sieving in CD2AP KO mice and underscored the importance of local factors in the development of glomerulosclerosis. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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210. Association of CD2AP with dynamic actin on vesicles in podocytes.
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Welsch, Thilo, Endlich, Nicole, Gökce, Gökmen, Doroshenko, Elena, Simpson, Jeremy C., Kriz, Wilhelm, Shaw, Andrey S., and Endlich, Karihans
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DEXTRAN ,GLUCANS ,BLOOD plasma substitutes ,CARBOHYDRATES ,GENETIC mutation ,RESPIRATORY organs - Abstract
The docking protein CD2AP (CD2-associated protein) serves a nonredundant function in podocytes as CD2AP knockout mice die of renal failure at the age of 6-7 wk. Furthermore, haploinsufficiency due to mutation of the CD2AP gene is associated with focal segmental glomerulosclerosis in humans. Although CD2AP has been shown to interact with proteins regulating actin polymerization, with proteins of the slit diaphragm, and with the endocytic machinery, its critical function in podocytes remains unclear. In conditionally immortalized mouse podocytes, we demonstrate that CD2AP colocalizes with cortactin and F-actin in spots of ⩽0.5-μm diameter. Confocal time-lapse microscopy in living podocytes expressing GFP-CD2AP or GFP-actin revealed that spots are motile, possess a limited lifetime, and are frequently associated with vesicles. A significant portion of spot-associated vesicles belongs to a later endosomal-sorting compartment, characterized by delayed uptake of fluorescent dextran (10 kDa) and by colocalization with Rab4, but not Rab5 and AP-2. Rapid accumulation of microinjected G-actin in spots and abrogation of spot motility by jasplakinolide demonstrate that spot movements depend on actin polymerization. Furthermore, a high turnover (half-time < 10 s) of CD2AP in spots was demonstrated by FRAP (fluorescence recovery after photobleaching). Our results demonstrate that CD2AP is associated with dynamic actin in a specific late endosomal compartment in podocytes, suggesting that CD2AP might be crucially involved in endosomal sorting and/or trafficking via regulation of actin assembly on vesicles. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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211. New Lamp Posts Allow for New Views of the Immunological Synapse.
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Raju, Saravanan and Shaw, Andrey S.
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IMMUNE system , *SYNAPSES , *IMAGING systems , *CELLULAR immunity , *HIGH resolution imaging - Abstract
Using new rapid, super-resolution imaging methods, Ritter et al. (2015) define the early events of immunological synapse formation and granule release. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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212. CRAF dimerization with ARAF regulates KRAS-driven tumor growth
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Venkatanarayan, Avinashnarayan, Liang, Jason, Yen, Ivana, Shanahan, Frances, Haley, Benjamin, Phu, Lilian, Verschueren, Erik, Hinkle, Trent B., Kan, David, Segal, Ehud, Long, Jason E., Lima, Tony, Liau, Nicholas P.D., Sudhamsu, Jawahar, Li, Jason, Klijn, Christiaan, Piskol, Robert, Junttila, Melissa R., Shaw, Andrey S., Merchant, Mark, Chang, Matthew T., Kirkpatrick, Donald S., and Malek, Shiva
- Abstract
KRAS, which is mutated in ∼30% of all cancers, activates the RAF-MEK-ERK signaling cascade. CRAF is required for growth of KRASmutant lung tumors, but the requirement for CRAF kinase activity is unknown. Here, we show that subsets of KRASmutant tumors are dependent on CRAF for growth. Kinase-dead but not dimer-defective CRAF rescues growth inhibition, suggesting that dimerization but not kinase activity is required. Quantitative proteomics demonstrates increased levels of CRAF:ARAF dimers in KRASmutant cells, and depletion of both CRAF and ARAF rescues the CRAF-loss phenotype. Mechanistically, CRAF depletion causes sustained ERK activation and induction of cell-cycle arrest, while treatment with low-dose MEK or ERK inhibitor rescues the CRAF-loss phenotype. Our studies highlight the role of CRAF in regulating MAPK signal intensity to promote tumorigenesis downstream of mutant KRASand suggest that disrupting CRAF dimerization or degrading CRAF may have therapeutic benefit.
- Published
- 2022
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213. Diffusion tensor MRI is sensitive to fibrotic injury in a mouse model of oxalate-induced chronic kidney disease.
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Virgincar, Rohan S., Wong, Aaron K., Barck, Kai H., Webster, Joshua D., Hung, Jeffrey, Caplazi, Patrick, Choy, Man Kin, Forrest, William F., Bell, Laura C., Crespigny, Alex J. de, Dunlap, Debra, Jones, Charles, Kim, Dong Eun, Weimer, Robby M., Shaw, Andrey S., Brightbill, Hans D., and Xie, Luke
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DIFFUSION magnetic resonance imaging , *CHRONIC kidney failure , *RENAL fibrosis , *DIFFUSION tensor imaging , *LABORATORY mice - Abstract
Chronic kidney disease (CKD) is characterized by inflammation and fibrosis in the kidney. Renal biopsies and estimated glomerular filtration rate (eGFR) remain the standard of care, but these endpoints have limitations in detecting the stage, progression, and spatial distribution of fibrotic pathology in the kidney. MRI diffusion tensor imaging (DTI) has emerged as a promising noninvasive technology to evaluate renal fibrosis in vivo both in clinical and preclinical studies. However, these imaging studies have not systematically identified fibrosis particularly deeper in the kidney where biopsy sampling is limited, or completed an extensive analysis of whole organ histology, blood biomarkers, and gene expression to evaluate the relative strengths and weaknesses of MRI for evaluating renal fibrosis. In this study, we performed DTI in the sodium oxalate mouse model of CKD. The DTI parameters fractional anisotropy, apparent diffusion coefficient, and axial diffusivity were compared between the control and oxalate groups with region of interest (ROI) analysis to determine changes in the cortex and medulla. In addition, voxel-based analysis (VBA) was implemented to systematically identify local regions of injury over the whole kidney. DTI parameters were found to be significantly different in the medulla by both ROI analysis and VBA, which also spatially matched with collagen III immunohistochemistry (IHC). The DTI parameters in this medullary region exhibited moderate to strong correlations with histology, blood biomarkers, hydroxyproline, and gene expression. Our results thus highlight the sensitivity of DTI to the heterogeneity of renal fibrosis and importance of whole kidney noninvasive imaging. NEW & NOTEWORTHY: Chronic kidney disease (CKD) can be characterized by inflammation and fibrosis of the kidney. Although standard of care methods have been limited in scope, safety, and spatial distribution, MRI diffusion tensor imaging (DTI) has emerged as a promising noninvasive technology to evaluate renal fibrosis in vivo. In this study, we performed DTI in an oxalate mouse model of CKD to systematically identify local kidney injury. DTI parameters strongly correlated with histology, blood biomarkers, hydroxyproline, and gene expression. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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214. Fidelity of t cell activation through multistep t cell receptor .... phosphorylation.
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Kersh, Ellen Neumeister, Shaw, Andrey S., and Allen, Paul M.
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T cell receptors , *ANTIGENS , *LIGANDS (Biochemistry) - Abstract
Examines the role of the ...component of the murine t cell receptor (TCR) in contributing to the fidelity of antigen recognition. How the TCR alpha-beta heterodimer interacts with ligands with high specifity but low affinity; Documentation of the molecular events that follow the engagement of the low-affinity receptor.
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- 1998
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215. Novel markers of normal and neoplastic human plasmacytoid dendritic cells
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Marafioti, Teresa, Paterson, Jennifer C., Ballabio, Erica, Reichard, Kaaren K., Tedoldi, Sara, Hollowood, Kevin, Dictor, Michael, Hansmann, Martin-Leo, Pileri, Stefano A., Dyer, Martin J., Sozzani, Silvano, Dikic, Ivan, Shaw, Andrey S., Petrella, Tony, Stein, Harald, Isaacson, Peter G., Facchetti, Fabio, and Mason, David Y.
- Abstract
Plasmacytoid dendritic cells (pDCs) are involved in innate immunity (eg, by secreting interferons) and also give rise to CD4+CD56+ hematodermic neoplasms. We report extensive characterization of human pDCs in routine tissue samples, documenting the expression of 19 immunohistologic markers, including signaling molecules (eg, BLNK), transcription factors (eg, ICSBP/IRF8 and PU.1), and Toll-like receptors (TLR7, TLR9). Many of these molecules are expressed in other cell types (principally B cells), but the adaptor protein CD2AP was essentially restricted to pDCs, and is therefore a novel immunohistologic marker for use in tissue biopsies. We found little evidence for activation-associated morphologic or phenotypic changes in conditions where pDCs are greatly increased (eg, Kikuchi disease). Most of the molecules were retained in the majority of pDC neoplasms, and 3 (BCL11A, CD2AP, and ICSBP/IRF8) were also commonly negative in leukemia cutis (acute myeloid leukemia in the skin), a tumor that may mimic pDC neoplasia. In summary, we have documented a range of molecules (notably those associated with B cells) expressed by pDCs in tissues and peripheral blood (where pDCs were detectable in cytospins at a frequency of < 1% of mononuclear cells) and also defined potential new markers (in particular CD2AP) for the diagnosis of pDC tumors.
- Published
- 2008
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216. Do T Cells Have a Cilium?
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Le Borgne, Marie and Shaw, Andrey S.
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MICROTUBULES , *CELLULAR signal transduction , *LYMPHOCYTES , *PHYSIOLOGY - Abstract
The article discusses the presence of microtubule structure that extend from cell surface enabling motility and signal transduction known as cilia in T-lymphocytes and informs that in previous studies cilia have not been found in lymphocytes.
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- 2013
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217. CD2AP is expressed with nephrin in developing podocytes and is found widely in mature kidney and elsewhere
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Li, Cong, Ruotsalainen, Vesa, Tryggvason, Karl, Shaw, Andrey S., and Miner, Jeffrey H.
- Abstract
CD2-associated protein (CD2AP) is an adapter molecule that can bind to the cytoplasmic domain of nephrin, a component of the glomerular slit diaphragm. Mice lacking CD2AP exhibit a congenital nephrotic syndrome characterized by extensive foot process effacement, suggesting that CD2AP-nephrin interactions are critical to maintaining slit diaphragm function. We have examined the patterns of expression of both CD2AP and nephrin in developing mouse and human kidney. Both proteins were first detected in developing podocytes at the capillary loop stage of glomerulogenesis and eventually became concentrated near the glomerular basement membrane. CD2AP was also observed diffusely in collecting duct and apically in many cells of proximal and distal tubule. Kidneys fromCd2ap−/− mice initially exhibited normal nephrin localization, but as the mice aged and foot processes became effaced, nephrin disappeared. In laminin-β2mutant mice exhibiting nephrotic syndrome, CD2AP in glomeruli was aberrantly localized in a primarily punctate pattern. Extensive extrarenal expression of CD2AP was observed in endothelial and epithelial cells, in many cases with a specific subcellular localization. Together, these results suggest that CD2AP is not only involved in maintaining the slit diaphragm but may also have a general role in maintaining specialized subcellular architecture. The severity of kidney disease in Cd2ap mutant mice may have eclipsed manifestation of defects in other tissues.
- Published
- 2000
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218. SAP Signaling: A Dual Mechanism of Action
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Le Borgne, Marie and Shaw, Andrey S.
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CELLULAR signal transduction , *IMMUNITY , *ADAPTOR proteins , *AMYLOID beta-protein , *GENETIC regulation , *CELLULAR control mechanisms - Abstract
In this issue of Immunity, , and show that the adaptor protein SAP regulates both positive and negative signals through SLAM receptors to stabilize intercellular contacts. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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219. Proline Residues in Cd28 and the Src Homology (Sh)3 Domain of Lck Are Required for T Cell Costimulation
- Author
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Holdorf, Amy D., Green, Jonathan M., Levin, Steven D., Denny, Michael F., Straus, David B., Link, Vinzenz, Changelian, Paul S., Allen, Paul M., and Shaw, Andrey S.
- Abstract
The Src family tyrosine kinases Lck and Fyn are critical for signaling via the T cell receptor. However, the exact mechanism of their activation is unknown. Recent crystal structures of Src kinases suggest that an important mechanism of kinase activation is via engagement of the Src homology (SH)3 domain by proline-containing sequences. To test this hypothesis, we identified several T cell membrane proteins that contain potential SH3 ligands. Here we demonstrate that Lck and Fyn can be activated by proline motifs in the CD28 and CD2 proteins, respectively. Supporting a role for Lck in CD28 signaling, we demonstrate that CD28 signaling in both transformed and primary T cells requires Lck as well as proline residues in CD28. These data suggest that Lck plays an essential role in CD28 costimulation.
- Published
- 1999
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220. Identification of an Interferon-γReceptor α Chain Sequence Required for JAK-1 Binding (∗)
- Author
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Kaplan, Daniel H., Greenlund, Andrew C., Tanner, J. William, Shaw, Andrey S., and Schreiber, Robert D.
- Abstract
We have shown previously that a four-amino acid block residing at positions 266-269 (LPKS) in the intracellular domain of the human interferon-γ(IFN-γ) receptor α chain is critical for IFN-γ-dependent tyrosine kinase activation and biologic response induction. Herein we show that this sequence is required for the constitutive attachment of the tyrosine kinase JAK-1. Using a vaccinia expression system, a receptor α chain-specific monoclonal antibody coprecipitated JAK-1 from cells coexpressing JAK-1 and either (a) wild type IFN-γreceptor α chain, (b) a receptor α chain truncation mutant containing only the first 59 intracellular domain amino acids, or (c) a receptor mutant containing alanine substitutions for the functionally irrelevant residues 272-275. In contrast, JAK-1 was not coprecipitated when coexpressed with a receptor α chain mutant containing alanine substitutions for the functionally critical residues 266-269 (LPKS). Mutagenesis of the LPKS sequence revealed that Pro-267 is the only residue obligatorily required for receptor function. In addition, Pro-267 is required for JAK-1 binding. These results thus identify a site in the IFN-γreceptor α chain required for constitutive JAK-1 association and establish that this association is critical for IFN-γsignal transduction.
- Published
- 1996
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221. TRP'ing up chronic kidney disease: Blockade of a specific calcium channel can slow chronic kidney disease progression.
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Jun-Jae Chung and Shaw, Andrey S.
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- *
CALCIUM channels , *KIDNEY diseases , *HYPERTENSION , *CHRONIC kidney failure , *TRP channels - Abstract
The article reports on the impact of blockade in calcium channel on chronic kidney disease (CKD). Topics discussed include several cause of chronic kidney disease such as obesity, hypertension and diabetes, increase in the risk of end-stage renal disease (ESRD) and role of transient receptor potential canonical-5 (TRPC5).
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- 2017
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222. Super-resolution Imaging of the Kidney Glomerulus in Health and Disease Conditions.
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Suleiman, Hani Y., Roth, Robyn, Miner, Jeffrey H., and Shaw, Andrey S.
- Published
- 2017
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223. Tweaking the Spines of Kinase Structures
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Ahuja, Lalima G., Hu, Jiancheng, Alexandr Kornev, Shaw, Andrey S., and Taylor, Susan S.
224. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis
- Author
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Smith, Stephen R., Kalra, Philip A., Lindsey, Thomas B., Alonso, Andrea S., Sparks, Matthew A., Adeyemo, Adebowale A., Jiang, Ruiji, Gbadegesin, Rasheed A., Wu, Guanghong, Phelan, Paul J., Winn, Michelle P., Conlon, Peter J., Howell, David N., Homstad, Alison, Malone, Andrew F., Charles Jennette, J., Webb, Nicholas J.A., Shaw, Andrey S., Hall, Gentzon, and Cetincelik, Umran
- Subjects
urogenital system ,urologic and male genital diseases ,female genital diseases and pregnancy complications ,3. Good health - Abstract
Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes including inherited genetic defects with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome, thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane findings. Secondary FSGS is known to develop in classic Alport Syndrome at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical findings at diagnosis were proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin glomerular basement membrane, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.
225. The Ick tyrosine protein kinase interacts with the cytoplasmic tail of the CD4 glycoprotein through its unique amino-terminal domain
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Shaw, Andrey S., primary, Amrein, Kurt E., additional, Hammond, Craig, additional, Stern, David F., additional, Sefton, Bartholomew M., additional, and Rose, John K., additional
- Published
- 1989
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226. All signals are go: Reviewing lymphocyte signal transduction Lymphocyte activation. Edited by Lawrence Samelson. Basel: S. Karger. (1994). 219 pp. $168.00
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Shaw, Andrey S
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227. A systems mechanism for KRAS mutant allele–specific responses to targeted therapy
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McFall, Thomas, Diedrich, Jolene K., Mengistu, Meron, Littlechild, Stacy L., Paskvan, Kendra V., Sisk-Hackworth, Laura, Moresco, James J., Shaw, Andrey S., and Stites, Edward C.
- Abstract
A weak KRASG13D-NF1 interaction explains why EGFR inhibitors show efficacy in certain CRC patients.
- Published
- 2019
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228. Kinase domain dimerization drives RIPK3-dependent necroptosis
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Raju, Saravanan, Whalen, Daniel M., Mengistu, Meron, Swanson, Carter, Quinn, John G., Taylor, Susan S., Webster, Joshua D., Newton, Kim, and Shaw, Andrey S.
- Abstract
Necroptotic cell death is promoted by the dimerization-dependent activation of the kinase RIPK3.
- Published
- 2018
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229. CAR'ing for the Skin.
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Shaw, Andrey S. and Huang, Yina
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IMMUNOLOGY , *IMMUNE response , *SKIN physiology , *TIGHT junctions , *CELL adhesion molecules , *IMMUNOGLOBULINS , *LANGERHANS cells , *JUNCTIONAL complexes (Epithelium) , *PROTEINS - Abstract
The article discusses two reports within the issue regarding immunology research in which both scientific teams demonstrate a part of the mechanism that alerts sentinel cells embedded in the skin and mucosa that it has been breached by a pathogen. Topics include an overview of the physiology of skin and various skin proteins, including the immunoglobulin superfamily (IgSF), which facilitates the transient opening of epithelial barriers to allow the passage of cells in tight junctions, and the junctional adhesion molecule-like proteins (JAMLs), which facilitates neutrophil chemotaxis across endothelial cells. Also discussed is the sentinel skin cell γδ, which is an epidermal T cell that responds to injury and infection when stimulated by a cellular adhesion protein.
- Published
- 2010
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230. Costimulation: Building an Immunological Synapse.
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Dustin, Michael L. and Shaw, Andrey S.
- Subjects
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IMMUNE system , *T cell receptors , *SYNAPSES , *CELL membranes - Abstract
Reports on the efforts to develop a method using costimulation to build an immunological synapse. How activation of the T cell is the central event in the development of immunity; The role of the T cell receptor (TCR); How efficient T cell activation requires engagement of at least two types of T cell surface receptors; Use of rafts, which are required for T cell activation, in stimulating growth of immunological synapses.
- Published
- 1999
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231. CD2AP Links Cortactin and Capping Protein at the Cell Periphery To Facilitate Formation of Lamellipodia.
- Author
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Jianping Zhaoa, Bruck, Serawit, Cemerski, Saso, Lei Zhang, Butler, Boyd, Dani, Adish, Cooper, John A., and Shaw, Andrey S.
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ACTIN research ,CYTOSKELETON ,PROTEIN kinases ,MEMBRANE proteins ,CELL migration - Abstract
Understanding the physiology of complex relationships between components of signaling pathways and the actin cytoskeleton is an important challenge. CD2AP is a membrane scaffold protein implicated in a variety of physiological and disease processes. The physiological function of CD2AP is unclear, but its biochemical interactions suggest that it has a role in dynamic actin assembly. Here, we report that CD2AP functions to facilitate the recruitment of actin capping protein (CP) to the Src kinase substrate, cortactin, at the cell periphery, and that this is necessary for formation of the short branched filaments that characterize lamellipodium formation and are required for cell migration. Superresolution fluorescence microscopy demonstrated that the efficient colocalization of CP and cortactin at the cell periphery required CD2AP. As both cortactin and CP function to enhance branched actin filament formation, CD2AP functions synergistically to enhance the function of both proteins. Our data demonstrate how the interplay between specialized actin regulatory molecules shapes the actin cytoskeleton. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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232. Kinase Suppressor of Ras 2 (KSR2) Regulates Resting Thermogenesis and Insulin Sensitivity.
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Costanzo-Garvey, Diane L., Pfluger, Paul, Stock, Jeffery L., Schreiner, Aimee, Hong, Eun-Gyoung, Volle, Deanna J., Treece, Tina, Wu, Ming-Hoi, Shaw, Andrey S., Ko, Hwi Jin, Mcneish, John, Kim, Jason K., Tschã-p, Matthias H., and Lewis, Robert E.
- Subjects
PROTEINS ,INSULIN resistance ,GLUCOSE ,METABOLISM ,PROTEIN kinases ,MICE - Abstract
Kinase Suppressor of Ras 1 and 2 (KSR1 and KSR2) are molecular scaffolds that regulate the intensity and duration of signaling through the Raf/MEK/ERK kinase cascade. KSR1[sup -/-] mice were lean but glucose intolerant. Homozygous disruption of KSR2 caused marked obesity, elevated plasma leptin and insulin levels, and intolerance to exogenous glucose and insulin. In hyperinsulinemic (2.5 mU/kg/min)-euglycemic clamp studies, the rate of glucose infused to maintain euglycemia (∼6 mM) was reduced by 60% in KSR2[sup -/-] mice as compared to wild-type (vet) mice. Basal hepatic glucose production (HGP) was significantly decreased in KSR2[sup -/-] mice, and hepatic insulin action, as reflected by insulin-mediated percent suppression of basal HGP, was reduced by more than 30%. Insulin-stimulated whole body glucose turnover was markedly decreased in KSR2[sup -/-] mice, indicating that KSR2 deletion caused insulin resistance in liver and peripheral tissues. Whole body glycolysis and glycogen plus lipid synthesis were similarly reduced in KSR2[sup -/-] mice. These data am consistent with the markedly reduced glycogen content in the livers and glycolytic muscle of KSR2[sup -/-] mice. Insulin-stimulated glucose uptake in skeletal muscle and adipose tissues was reduced b), 50-80% in KSR2[sup -/-] mice. Surprisingly, KSR2[sup -/-] mice are hypophagic, more physically active and exhibit a decreased respiratory quotient in comparison to wt mice. However, total energy expenditure of KSR2[sup -/-] mice is significantly lower compared to wt mice. We conclude that compensatory processes controlled by the central nervous system are still intact, hut not sufficient to restore a severely decreased resting thermogenesis. These data indicate that KSR proteins affect insulin sensitivity and glucose metabolism in peripheral tissue. Coupled with the potent effect of KSR proteins in regulating Raf and MEK activation, these observations suggest a previously unidentified, but physiologically important, role for these molecular scaffolds in regulating cellular metabolism. [ABSTRACT FROM AUTHOR]
- Published
- 2007
233. The Molecular Scaffold Kinase Suppressor of Ras 1 Is a Modifier of RasV12-Induced and Replicative Senescence.
- Author
-
Kortum, Robert L., Johnson, Heidi J., Costanzo, Diane L., Volle, Deanna J., Razidlo, Gina L., Fusello, Angela M., Shaw, Andrey S., and Lewis, Robert E.
- Subjects
FIBROBLASTS ,TUMOR suppressor proteins ,CELLS ,FOCAL adhesion kinase ,AGING - Abstract
In primary mouse embryo fibroblasts (MEFs), oncogenic Ras induces growth arrest via Raf/MEK/extracellular signal-regulated kinase (ERK)-mediated activation of the p19
ARF /p53 and INK4/Rb tumor suppressor pathways. Ablation of these same pathways causes spontaneous immortalization in MEFs, and oncogenic transformation by Ras requires ablation of one or both of these pathways. We show that Kinase Suppressor of Ras 1 (KSR1), a molecular scaffold for the Raf/MEK/ERK cascade, is necessary for RasV12 -induced senescence, and its disruption enhances primary MEF immortalization. RasV12 failed to induce p53, p19ARF , p16INK4a , and p15INK4b expression in KSR1-/- MEFs and increased proliferation instead of causing growth arrest. Reintroduction of wild-type KSR1, but not a mutated KSR1 construct unable to bind activated ERK, rescued RasV12 -induced senescence. On continuous culture, deletion of KSR1 accelerated the establishment of spontaneously immortalized cultures and increased the proportion of cultures escaping replicative crisis. Despite enhancing escape from both RasV12 -induced and replicative senescence, however, both primary and immortalized KSR1-/- MEFs are completely resistant to RasV12 -induced transformation. These data show that escape from senescence is not necessarily a precursor for oncogenic transformation. Furthermore, these data indicate that KSR1 is a member of a unique class of proteins whose deletion blocks both senescence and transformation. [ABSTRACT FROM AUTHOR]- Published
- 2006
- Full Text
- View/download PDF
234. Calmodulin and PI(3,4,5)P3cooperatively bind to the Itk pleckstrin homology domain to promote efficient calcium signaling and IL-17A production
- Author
-
Wang, Xinxin, Boyken, Scott E., Hu, Jiancheng, Xu, Xiaolu, Rimer, Ryan P., Shea, Madeline A., Shaw, Andrey S., Andreotti, Amy H., and Huang, Yina H.
- Abstract
Calcium and lipids stimulate the kinase Itk through the same domain to promote proinflammatory T cell signaling.
- Published
- 2014
- Full Text
- View/download PDF
235. Proteinuria precedes podocyte abnormalities in Lamb2–/– mice, implicating the glomerular basement membrane as an albumin barrier.
- Author
-
Jarad, George, Cunningham, Jeanette, Shaw, Andrey S., and Miner, Jeffrey H.
- Published
- 2006
- Full Text
- View/download PDF
236. Proteinuria precedes podocyte abnormalities inLamb2-/- mice, implicating the glomerular basement membrane as an albumin barrier.
- Author
-
Jarad, George, Cunningham, Jeanette, Shaw, Andrey S, and Miner, Jeffrey H
- Subjects
- *
ALBUMINURIA , *ANIMAL experimentation , *BIOLOGICAL models , *EPITHELIAL cells , *FERRITIN , *KIDNEY glomerulus , *MEMBRANE proteins , *BASAL lamina , *MICE , *NEPHROTIC syndrome , *PROTEINURIA , *RESEARCH funding , *SCANNING electron microscopy , *PHYSIOLOGY - Abstract
Primary defects in either podocytes or the glomerular basement membrane (GBM) cause proteinuria, a fact that complicates defining the barrier to albumin. Laminin beta2 (LAMB2) is a GBM component required for proper functioning of the glomerular filtration barrier. To investigate the GBM's role in glomerular filtration, we characterized GBM and overlying podocyte architecture in relation to development and progression of proteinuria in Lamb2-/- mice, which model Pierson syndrome, a rare congenital nephrotic syndrome. We found ectopic deposition of several laminins and mislocalization of anionic sites in the GBM, which together suggest that the Lamb2-/- GBM is severely disorganized, although it is ultrastructurally intact. Importantly, albuminuria was detectable shortly after birth and preceded podocyte foot process effacement and loss of slit diaphragms by at least 7 days. Expression and localization of slit diaphragm and foot process-associated proteins appeared normal at early stages. GBM permeability to the electron-dense tracer ferritin was dramatically elevated in Lamb2-/- mice, even before widespread foot process effacement. Increased ferritin permeability was not observed in nephrotic CD2-associated protein-null (Cd2ap-/-) mice, which have a primary podocyte defect. Together these data show that the GBM serves as a barrier to protein in vivo and that the glomerular slit diaphragm alone is not sufficient to prevent the passage of albumin into the urinary space. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
237. The c-SMAC: sorting it all out (or in).
- Author
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Lin, Joseph, Miller, Mark J., and Shaw, Andrey S.
- Subjects
- *
T cells , *LYMPHOCYTES , *PROTEINS , *IMMUNOLOGY , *CELL membranes , *CELL receptors - Abstract
I cells integrate and transduce the key signals necessary to mount an appropriate immune response. To do this, they rely on both secreted factors as well as physical cell-cell contact. Much attention has focused on the organization of proteins at the contact area between a T cell and an antigen-presenting cell, known as the immunological synapse. It has been shown in vitro that proteins segregate into two distinct regions within this contact area, a central area referred to as the c-SMAC, where the I cell receptor and associated signaling molecules are enriched, and a peripheral region called the p-SMAC containing LFA- 1 and the scaffolding protein talin. Whether or not these structures form in vivo and how they function in T cell activation remain issues of great interest, Here, we review recently published work and propose several possible functions for the role of the c-SMAC in T cell activation. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
238. The Mesangial cell - the glomerular stromal cell.
- Author
-
Avraham, Shimrit, Korin, Ben, Chung, Jun-Jae, Oxburgh, Leif, and Shaw, Andrey S.
- Subjects
- *
STROMAL cells , *CELL differentiation , *VASCULAR smooth muscle , *CELL physiology , *MUSCLE cells , *KIDNEY diseases , *FIBROSIS , *CHRONIC kidney failure , *RESEARCH , *RESEARCH methodology , *EVALUATION research , *COMPARATIVE studies , *CONNECTIVE tissue cells , *KIDNEY glomerulus - Abstract
Mesangial cells are stromal cells that are important for kidney glomerular homeostasis and the glomerular response to injury. A growing body of evidence demonstrates that mesenchymal stromal cells, such as stromal fibroblasts, pericytes and vascular smooth muscle cells, not only specify the architecture of tissues but also regulate developmental processes, vascularization and cell fate specification. In addition, through crosstalk with neighbouring cells and indirectly through the remodelling of the matrix, stromal cells can regulate a variety of processes such as immunity, inflammation, regeneration and in the context of maladaptive responses - fibrosis. Insights into the molecular phenotype of kidney mesangial cells suggest that they are a specialized stromal cell of the glomerulus. Here, we review our current understanding of mesenchymal stromal cells and discuss how it informs the function of mesangial cells and their role in disease. These new insights could lead to a better understanding of kidney disease pathogenesis and the development of new therapies for chronic kidney disease. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
239. Scaffolds, adaptors and linkers of TCR signaling: theory and practice
- Author
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Burack, W. Richard, Cheng, Alec M., and Shaw, Andrey S.
- Subjects
- *
PROTEINS , *ANTIGENS , *IMMUNOLOGY - Abstract
Four non-enzymatic proteins form the structural core of the TCR signaling machinery, linking antigen-receptor activation to signaling. These four proteins, each with well defined protein–protein interaction domains, include three ‘scaffolds’ (LAT, SLP-76 and SLAP-130/Fyb/ADAP and a ‘pure adaptor’ (GADS). The biological functions of many distinct protein–protein interaction domains have been dissected through a methodological series of knockout and reconstitution experiments. In reviewing these recent advances, we attempt to address two questions often asked by immunologists not familiar with the field: what do scaffolds/adaptors/linkers do; and what do these terms mean? [Copyright &y& Elsevier]
- Published
- 2002
- Full Text
- View/download PDF
240. Immature CD4+CD8+ Thymocytes Form a Multifocal Immunological Synapse with Sustained Tyrosine Phosphorylation
- Author
-
Hailman, Eric, Burack, W. Richard, Shaw, Andrey S., Dustin, Michael L., and Allen, Paul M.
- Subjects
- *
SYNAPSES , *PHOSPHORYLATION , *MAJOR histocompatibility complex - Abstract
The immunological synapse formed during mature T cell activation consists of a central cluster of TCR and MHC molecules surrounded by a ring of LFA-1 and ICAM-1. We examined synapse formation in thymocytes undergoing activation in a lipid bilayer system by following the movement of fluorescent MHC and ICAM-1 molecules. Immature CD4+CD8+ thymocytes formed a decentralized synapse with multiple foci of MHC accumulation corresponding to areas of exclusion of ICAM-1. The MHC clusters and ICAM-1 holes were mobile and transient and correlated with active and sustained signaling, as shown by staining with antibodies against phosphotyrosine and activated Lck. Our findings show that signaling in immature thymocytes can result from a novel, multifocal pattern of receptor accumulation. [Copyright &y& Elsevier]
- Published
- 2002
- Full Text
- View/download PDF
241. New roles revealed for T cells and DCs in glomerulonephritis.
- Author
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Kim, Alfred H. J., Markiewicz, Mary A., and Shaw, Andrey S.
- Subjects
- *
LYMPHOCYTES , *IMMUNOGLOBULINS , *KIDNEY glomerulus diseases , *ENZYME activation , *IMMUNE complexes , *IMMUNE complex diseases , *COMPLEMENT activation - Abstract
Little is known about the potential role of T cells in the inflammatory renal disease glomerulonephritis (GN). GN has been historically viewed as a product of immune complex-mediated complement activation, and the presence of autoantibodies made identifying T cell-specific effector contributions difficult to elucidate. In this issue of the JCI, Heymann et al. generate what they believe to be a novel, transgenic murine model of GN, demonstrating a direct role for CD8+ T cells, activated CD4+ T cells, and DCs in the pathogenesis of GN (see the related article beginning on page 1286). [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
242. Book review.
- Author
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Shaw, Andrey S.
- Subjects
- LYMPHOCYTE Activation (Book)
- Abstract
Reviews the book `Lymphocyte Activation,' edited by Lawrence Samuelson.
- Published
- 1995
243. The adaptor molecule CD2AP in CD4 T cells modulates differentiation of follicular helper T cells during chronic LCMV infection.
- Author
-
Raju, Saravanan, Kometani, Kohei, Kurosaki, Tomohiro, Shaw, Andrey S., and Egawa, Takeshi
- Subjects
- *
CD4 antigen , *T helper cells , *IMMUNE response , *LYMPHOCYTES , *LABORATORY mice - Abstract
CD4 T cell-mediated help to CD8 T cells and B cells is a critical arm of the adaptive immune system required for control of pathogen infection. CD4 T cells express cytokines and co-stimulatory molecules that support a sustained CD8 T cell response and also enhance generation of protective antibody by germinal center B cells. However, the molecular components that modulate CD4 T cell functions in response to viral infection or vaccine is incompletely understood. Here we demonstrate that inactivation of the signaling adaptor CD2-associated protein (CD2AP) promotes CD4 T cell differentiation towards the follicular helper lineage, leading to enhanced control of viral infection by augmented germinal center response in chronic lymphocytic choriomeningitis virus (LCMV) infection. The enhanced follicular helper differentiation is associated with extended duration of TCR signaling and enhanced cytokine production of CD2AP-deficient CD4 T cells specifically under TH1 conditions, while neither prolonged TCR signaling nor enhanced follicular helper differentiation was observed under conditions that induce other helper effector subsets. Despite the structural similarity between CD2AP and the closely related adaptor protein CIN85, we observed defective antibody-mediated control of chronic LCMV infection in mice lacking CIN85 in T cells, suggesting non-overlapping and potentially antagonistic roles for CD2AP and CIN85. These results suggest that tuning of TCR signaling by targeting CD2AP improves protective antibody responses in viral infection. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
244. Homozygous KSR1 deletion attenuates morbidity but does not prevent tumor development in a mouse model of RAS-driven pancreatic cancer.
- Author
-
Germino, Elizabeth A., Miller, Joseph P., Diehl, Lauri, Swanson, Carter J., Durinck, Steffen, Modrusan, Zora, Miner, Jeffrey H., and Shaw, Andrey S.
- Subjects
- *
DELETION mutation , *PANCREATIC cancer , *HOMOZYGOSITY , *MITOGEN-activated protein kinases , *CELLULAR signal transduction , *LABORATORY mice - Abstract
Given the frequency with which MAP kinase signaling is dysregulated in cancer, much effort has been focused on inhibiting RAS signaling for therapeutic benefit. KSR1, a pseudokinase that interacts with RAF, is a potential target; it was originally cloned in screens for suppressors of constitutively active RAS, and its deletion prevents RAS-mediated transformation of mouse embryonic fibroblasts. In this work, we used a genetically engineered mouse model of pancreatic cancer to assess whether KSR1 deletion would influence tumor development in the setting of oncogenic RAS. We found that Ksr1-/- mice on this background had a modest but significant improvement in all-cause morbidity compared to Ksr1+/+ and Ksr1+/- cohorts. Ksr1-/- mice, however, still developed tumors, and precursor pancreatic intraepithelial neoplastic (PanIN) lesions were detected within a similar timeframe compared to Ksr1+/+ mice. No significant differences in pERK expression or in proliferation were noted. RNA sequencing also did not reveal any unique genetic signature in Ksr1-/- tumors. Further studies will be needed to determine whether and in what settings KSR inhibition may be clinically useful. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
245. The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier.
- Author
-
Schell, Christoph, Rogg, Manuel, Suhm, Martina, Helmstädter, Martin, Sellung, Dominik, Mako Yasuda-Yamahara, Kretz, Oliver, Küttner, Victoria, Suleiman, Hani, Kollipara, Laxmikanth, Zahedi, René P., Sickmann, Albert, Eimer, Stefan, Shaw, Andrey S., Kramer-Zucker, Albrecht, Mariko Hirano-Kobayashi, Takaya Abe, Shinichi Aizawa, Grahammer, Florian, and Hartleben, Björn
- Subjects
- *
ACTOMYOSIN , *GLOMERULAR filtration rate , *KIDNEY function tests , *ADHESION , *MASS spectrometry - Abstract
Podocytes form the outer part of the glomerular filter, where they have to withstand enormous transcapillary filtration forces driving glomerular filtration. Detachment of podocytes from the glomerular basement membrane precedes most glomerular diseases. However, little is known about the regulation of podocyte adhesion in vivo. Thus, we systematically screened for podocyte-specific focal adhesome (FA) components, using genetic reporter models in combination with iTRAQ-based mass spectrometry. This approach led to the identification of FERM domain protein EPB41L5 as a highly enriched podocyte-specific FA component in vivo. Genetic deletion of Epb41l5 resulted in severe proteinuria, detachment of podocytes, and development of focal segmental glomerulosclerosis. Remarkably, by binding and recruiting the RhoGEF ARGHEF18 to the leading edge, EPB41L5 directly controls actomyosin contractility and subsequent maturation of focal adhesions, cell spreading, and migration. Furthermore, EPB41L5 controls matrix-dependent outside-in signaling by regulating the focal adhesome composition. Thus, by linking extracellular matrix sensing and signaling, focal adhesion maturation, and actomyosin activation EPB41L5 ensures the mechanical stability required for podocytes at the kidney filtration barrier. Finally, a diminution of EPB41L5-dependent signaling programs appears to be a common theme of podocyte disease, and therefore offers unexpected interventional therapeutic strategies to prevent podocyte loss and kidney disease progression. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
246. NKG2D-NKG2D Ligand Interaction Inhibits the Outgrowth of Naturally Arising Low-Grade B Cell Lymphoma In Vivo.
- Author
-
Raju, Saravanan, Kretzmer, Lena Z., Koues, Olivia I., Payton, Jacqueline E., Oltz, Eugene M., Cashen, Amanda, Polic, Bojan, Schreiber, Robert D., Shaw, Andrey S., and Markiewicz, Mary A.
- Subjects
- *
LIGANDS (Biochemistry) , *B cell lymphoma , *IMMUNITY , *CELL transformation , *TUMOR suppressor proteins - Abstract
It is now clear that recognition of nascent tumors by the immune system is critical for survival of the host against cancer. During cancer immunoediting, the ability of the tumor to escape immune recognition is important for tumor development. The immune system recognizes tumors via the presence of classical Ags and also by conserved innate mechanisms. One of these mechanisms is the NKG2D receptor that recognizes ligands whose expression is induced by cell transformation. In this study, we show that in NKG2D receptor-deficient mice, increasing numbers of B cells begin to express NKG2D ligands as they age. Their absence in wild-type mice suggests that these cells are normally cleared by NKG2D-expressing cells. NKG2D-deficient mice and mice constitutively expressing NKG2D ligands had increased incidence of B cell tumors, confirming that the inability to clear NKG2D ligand-expressing cells was important in tumor suppression and that NKG2D ligand expression is a marker of nascent tumors. Supporting a role for NKG2D ligand expression in controlling the progression of early-stage B cell lymphomas in humans, we found higher expression of a microRNA that inhibits human NKG2D ligand expression in tumor cells from high-grade compared with low-grade follicular lymphoma patients. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
247. A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis.
- Author
-
Haiyang Yu, Mykyta Artomov, Brähler, Sebastian, Stander, M. Christine, Shamsan, Ghaidan, Sampson, Matthew G., White, J. Michael, Kretzler, Matthias, Miner, Jeffrey H., Jain, Sanjay, Winkler, Cheryl A., Mitra, Robi D., Kopp, Jeffrey B., Daly, Mark J., Shaw, Andrey S., Yu, Haiyang, and Artomov, Mykyta
- Subjects
- *
GLOMERULOSCLEROSIS , *DISEASE susceptibility , *KIDNEY diseases , *APOLIPOPROTEINS , *HEALTH of African Americans , *GENETICS , *ANIMAL experimentation , *CELL culture , *GENETIC polymorphisms , *GENETIC techniques , *GLOMERULONEPHRITIS , *MICE , *RESEARCH funding , *CASE-control method , *SEQUENCE analysis - Abstract
Focal segmental glomerulosclerosis (FSGS) is a syndrome that involves kidney podocyte dysfunction and causes chronic kidney disease. Multiple factors including chemical toxicity, inflammation, and infection underlie FSGS; however, highly penetrant disease genes have been identified in a small fraction of patients with a family history of FSGS. Variants of apolipoprotein L1 (APOL1) have been linked to FSGS in African Americans with HIV or hypertension, supporting the proposal that genetic factors enhance FSGS susceptibility. Here, we used sequencing to investigate whether genetics plays a role in the majority of FSGS cases that are identified as primary or sporadic FSGS and have no known cause. Given the limited number of biopsy-proven cases with ethnically matched controls, we devised an analytic strategy to identify and rank potential candidate genes and used an animal model for validation. Nine candidate FSGS susceptibility genes were identified in our patient cohort, and three were validated using a high-throughput mouse method that we developed. Specifically, we introduced a podocyte-specific, doxycycline-inducible transactivator into a murine embryonic stem cell line with an FSGS-susceptible genetic background that allows shRNA-mediated targeting of candidate genes in the adult kidney. Our analysis supports a broader role for genetic susceptibility of both sporadic and familial cases of FSGS and provides a tool to rapidly evaluate candidate FSGS-associated genes. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
248. Albumin-associated free fatty acids induce macropinocytosis in podocytes.
- Author
-
Jun-Jae Chung, Huber, Tobias B., Gödel, Markus, Jarad, George, Hartleben, Björn, Kwoh, Christopher, Keil, Alexander, Karpitskiy, Aleksey, Jiancheng Hu, Huh, Christine J., Cella, Marina, Gross, Richard W., Miner, Jeffrey H., and Shaw, Andrey S.
- Subjects
- *
ALBUMINS , *FATTY acids , *NEPHROTIC syndrome , *PROTEINURIA , *KIDNEY diseases - Abstract
Podocytes are specialized epithelial cells in the kidney glomerulus that play important structural and functional roles in maintaining the filtration barrier. Nephrotic syndrome results from a breakdown of the kidney filtration barrier and is associated with proteinuria, hyperlipidemia, and edema. Additionally, podocytes undergo changes in morphology and internalize plasma proteins in response to this disorder. Here, we used fluid-phase tracers in murine models and determined that podocytes actively internalize fluid from the plasma and that the rate of internalization is increased when the filtration barrier is disrupted. In cultured podocytes, the presence of free fatty acids (FFAs) associated with serum albumin stimulated macropinocytosis through a pathway that involves FFA receptors, the Gβ/Gγ complex, and RAC1. Moreover, mice with elevated levels of plasma FFAs as the result of a high-fat diet were more susceptible to Adriamycin-induced proteinuria than were animals on standard chow. Together, these results support a model in which podocytes sense the disruption of the filtration barrier via FFAs bound to albumin and respond by enhancing fluid-phase uptake. The response to FFAs may function in the development of nephrotic syndrome by amplifying the effects of proteinuria. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
249. Allosteric Activation of Functionally Asymmetric RAF Kinase Dimers.
- Author
-
Hu, Jiancheng, Stites, Edward?C., Yu, Haiyang, Germino, Elizabeth?A., Meharena, Hiruy?S., Stork, Philip?J.S., Kornev, Alexandr?P., Taylor, Susan?S., and Shaw, Andrey?S.
- Subjects
- *
ALLOSTERIC regulation , *RAF genes , *PROTEIN kinases , *CELL growth , *DIMERIZATION , *AUTOPHOSPHORYLATION - Abstract
Summary: Although RAF kinases are critical for controlling cell growth, their mechanism of activation is incompletely understood. Recently, dimerization was shown to be important for activation. Here we show that the dimer is functionally asymmetric with one kinase functioning as an activator to stimulate activity of the partner, receiver kinase. The activator kinase did not require kinase activity but did require N-terminal phosphorylation that functioned allosterically to induce cis-autophosphorylation of the receiver kinase. Based on modeling of the hydrophobic spine assembly, we also engineered a constitutively active mutant that was independent of Ras, dimerization, and activation-loop phosphorylation. As N-terminal phosphorylation of BRAF is constitutive, BRAF initially functions to activate CRAF. N-terminal phosphorylation of CRAF was dependent on MEK, suggesting a feedback mechanism and explaining a key difference between BRAF and CRAF. Our work illuminates distinct steps in RAF activation that function to assemble the active conformation of the RAF kinase. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
250. RAE1ε Ligand Expressed on Pancreatic Islets Recruits NKG2D Receptor-Expressing Cytotoxic T Cells Independent of T Cell Receptor Recognition
- Author
-
Markiewicz, Mary A., Wise, Erica L., Buchwald, Zachary S., Pinto, Amelia K., Zafirova, Biljana, Polic, Bojan, and Shaw, Andrey S.
- Subjects
- *
LIGANDS (Biochemistry) , *ISLANDS of Langerhans , *CYTOTOXIC T cells , *T cell receptors , *LYMPHOCYTES , *LABORATORY mice , *TRETINOIN - Abstract
Summary: The mechanisms by which cytotoxic T lymphocytes (CTLs) enter and are retained in nonlymphoid tissue are not well characterized. With a transgenic mouse expressing the NKG2D ligand retinoic acid early transcript 1ε (RAE1ε) in β-islet cells of the pancreas, we found that RAE1 expression was sufficient to induce the recruitment of adoptively transferred CTLs to islets. This was dependent on NKG2D expression by the CTLs and independent of antigen recognition. Surprisingly, the recruitment of CTLs resulted in the subsequent recruitment of a large number of endogenous lymphocytes. Whereas transgenic mice did not develop diabetes, RAE1 expression was sufficient to induce insulitis in older, unmanipulated transgenic mice that was enhanced by viral infection and pancreatic inflammation. These results demonstrate that the expression of an NKG2D ligand in islets is sufficient to recruit CTLs regardless of their antigen specificity and to induce insulitis. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
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