25 results on '"Sorensen, Lise K."'
Search Results
2. Correction: Activation of NFAT by HGF and IGF-1 via ARF6 and its effector ASAP1 promotes uveal melanoma metastasis
- Author
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Richards, Jackson R., Shin, Donghan, Pryor, Rob, Sorensen, Lise K., Sun, Zhonglou, So, Won Mi, Park, Garam, Wolff, Roger, Truong, Amanda, McMahon, Martin, Grossmann, Allie H., Harbour, J. William, Zhu, Weiquan, Odelberg, Shannon J., and Yoo, Jae Hyuk
- Published
- 2023
- Full Text
- View/download PDF
3. Netrins Promote Developmental and Therapeutic Angiogenesis
- Author
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Wilson, Brent D., Park, Kye Won, Suli, Arminda, Sorensen, Lise K., Larrieu-Lahargue, Fréderic, Urness, Lisa D., Suh, Wonhee, Asai, Jun, Thorne, Tina, Silver, Marcy, Thomas, Kirk R., Chien, Chi-Bin, Losordo, Douglas W., and Li, Dean Y.
- Published
- 2006
4. The Axonal Attractant Netrin-1 Is an Angiogenic Factor
- Author
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Park, Kye Won, Crouse, Dana, Lee, Mark, Karnik, Satyajik K., Sorensen, Lise K., Murphy, Kelly J., Kuo, Calvin J., Li, Dean Y., and Majerus, Philip W.
- Published
- 2004
5. Defective Angiogenesis in Mice Lacking Endoglin
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Li, Dean Y., Sorensen, Lise K., Brooke, Benjamin S., Urness, Lisa D., Davis, Elaine C., Taylor, Douglas G., Boak, Beth B., and Wendel, Daniel P.
- Published
- 1999
6. Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy
- Author
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Zhu, Weiquan, Shi, Dallas S., Winter, Jacob M., Rich, Bianca E., Tong, Zongzhong, Sorensen, Lise K., Zhao, Helong, Huang, Yi, Tai, Zhengfu, Mleynek, Tara M., Yoo, Jae Hyuk, Dunn, Christine, Ling, Jing, Richards, Jackson R. Bergquist, Jake A., Jiang, Amanda, Lesniewski, Lisa A., Ward, M. Elizabeth Hartnet Diane M., Mueller, Alan L., Ostanin, Kirill, Thomas, Kirk R., Odelberg, Shannon J., and Li, Dean Y.
- Subjects
Diabetic retinopathy -- Genetic aspects -- Research ,Vascular endothelial growth factor -- Research ,Binding proteins -- Research ,Cellular signal transduction -- Research ,Health care industry - Abstract
The devastating sequelae of diabetes mellitus include microvascular permeability, which results in retinopathy. Despite clinical and scientific advances, there remains a need for new approaches to treat retinopathy. Here, we have presented a possible treatment strategy, whereby targeting the small GTPase ARF6 alters VEGFR2 trafficking and reverses signs of pathology in 4 animal models that represent features of diabetic retinopathy and in a fifth model of ocular pathological angiogenesis. Specifically, we determined that the same signaling pathway utilizes distinct GEFs to sequentially activate ARF6, and these GEFs exert distinct but complementary effects on VEGFR2 trafficking and signal transduction. ARF6 activation was independently regulated by 2 different ARF GEFs - ARNO and GEP100. Interaction between VEGFR2 and ARNO activated ARF6 and stimulated VEGFR2 internalization, whereas a VEGFR2 interaction with GEP100 activated ARF6 to promote VEGFR2 recycling via coreceptor binding. Intervening in either pathway inhibited VEGFR2 signal output. Finally, using a combination of in vitro, cellular, genetic, and pharmacologic techniques, we demonstrated that ARF6 is pivotal in VEGFR2 trafficking and that targeting ARF6-mediated VEGFR2 trafficking has potential as a therapeutic approach for retinal vascular diseases such as diabetic retinopathy., Introduction Over 25 million people in the United States have diabetes mellitus (1) and are prone to suffer from its devastating sequelae. The metabolic derangements seen in diabetes lead to [...]
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- 2017
- Full Text
- View/download PDF
7. Vascular Robo4 restricts proangiogenic VEGF signaling in breast
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Marlow, Rebecca, Binnewies, Mikhail, Sorensen, Lise K., Monica, Stefanie D., Strickland, Phyllis, Forsberg, E. Camilla, Li, Dean Y., Hinck, Lindsay, and Martin, Gail
- Published
- 2010
8. Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability
- Author
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Zhu, Weiquan, London, Nyall R., Gibson, Christopher C., Davis, Chadwick T., Tong, Zongzhong, Sorensen, Lise K., Shi, Dallas S., Guo, Jinping, Smith, Matthew C.P., Grossmann, Allie H., Thomas, Kirk R., and Li, Dean Y.
- Subjects
Inflammation -- Mediators ,Immune response -- Observations ,Cellular signal transduction -- Research ,Interleukins -- Testing ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
The innate immune response is essential for combating infectious disease. Macrophages and other cells respond to infection by releasing cytokines, such as interleukin-1β (IL-1β), which in turn activate a well-described, [...]
- Published
- 2012
- Full Text
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9. Novel Approach for Endothelializing Vascular Devices: Understanding and Exploiting Elastin–Endothelial Interactions
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Wilson, Brent D., Gibson, Christopher C., Sorensen, Lise K., Guilhermier, Margaret Yoklavich, Clinger, Melissa, Kelley, Linda L., Shiu, Yan-Ting E., and Li, Dean Y.
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- 2011
- Full Text
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10. Robo4 is a vascular-specific receptor that inhibits endothelial migration
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Park, Kye Won, Morrison, Clayton M., Sorensen, Lise K., Jones, Christopher A., Rao, Yi, Chien, Chin-Bin, Wu, Jane Y., Urness, Lisa D., and Li, Dean Y.
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Axons -- Research ,Cell migration -- Research ,Developmental biology -- Research ,Endothelium -- Research ,Cells -- Motility ,Cells -- Research ,Biological sciences - Abstract
Guidance and patterning of axons are orchestrated by cell-surface receptors and ligands that provide directional cues. Interactions between the Robo receptor and Slit ligand families of proteins initiate signaling cascades that repel axonal outgrowth. Although the vascular and nervous systems grow as parallel networks, the mechanisms by which the vascular endothelial cells are guided to their appropriate positions remain obscure. We have identified a putative Robo homologue, Robo4, based on its differential expression in mutant mice with defects in vascular sprouting. In contrast to known neuronal Robo family members, the arrangement of the extracellular domains of Robo4 diverges significantly from that of all other Robo family members. Moreover, Robo4 is specifically expressed in the vascular endothelium during murine embryonic development. We show that Robo4 binds Slit and inhibits cellular migration in a heterologous expression system, analogous to the role of known Robo receptors in the nervous system. Immunoprecipitation studies indicate that Robo4 binds to Mena, a known effector of Robo-Slit signaling. Finally, we show that Robo4 is the only Robo family member expressed in primary endothelial cells and that application of Slit inhibits their migration. These data demonstrate that Robo4 is a bona fide member of the Robo family and may provide a repulsive cue to migrating endothelial cells during vascular development. Keywords: Vascular development; Angiogenesis; Endothelial migration; Vascular sprouting; Activin receptor-like kinase 1 (Alk1); HHT; Neuronal/vascular guidance; Roundabout (Robo); Slit; Vascular patterning
- Published
- 2003
11. Loss of distinct arterial and venous boundaries in mice lacking endoglin, a vascular-specific TGF[beta] coreceptor
- Author
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Sorensen, Lise K., Brooke, Benjamin S., Li, Dean Y., and Urness, Lisa D.
- Subjects
Arteriovenous malformations -- Research ,Biological sciences - Abstract
Several characteristic morphological and functional differences distinguish arteries from veins. It was thought that hemodynamic forces shaped these differences; however, increasing evidence suggests that morphogenetic programs play a central role in blood vessel differentiation. Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by the inappropriate fusion of arterioles with venules. The genes implicated in this disease, ALK1 and endoglin, may be involved in defining the fundamental boundaries between arteries and veins. We previously showed that mice lacking Alk1 lost structural, molecular, and functional distinctions between arteries and veins [Nat. Genet. 26 (2000), 328]. Here, we report that mice lacking endoglin develop arterial-venous malformations and fail to confine intraembryonic hematopoiesis to arteries. In contrast to Alk1 mutants, endoglin mutants do not show profound vessel dilation or downregulation of arterial ephrinB2. Finally, our data indicate that a failure in cardiac cushion formation observed in both strains may be secondary to the peripheral vasculature defect. The phenotypic similarities, yet reduced severity, implicates endoglin as an accessory coreceptor that specifically modulates Alk1 signaling. We propose that endoglin and Alk1 are necessary for the maintenance of distinct arterial-venous vascular beds and that attenuation of the Alk1 signaling pathway is the precipitating event in the etiology of HHT. Keywords: Alk1; Acvrl1: Endoglin: Hereditary hemorrhagic telangiectasia (HHT); Arteriovenous malformations: Arteriovenous identity
- Published
- 2003
12. Elastin is an essential determinant of arterial morphogenesis
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Li, Dean Y., Brooke, Benjamin, Davis, Elaine C., Mecham, Robert P., Sorensen, Lise K., Boak, Beth B., Eichwald, Ernst, and Keating, Mark T.
- Published
- 1998
13. Methionine for valine substitution in exon 17 of the insulin receptor gene in a pedigree with familial NIDDM
- Author
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Elbein, Steven C., Sorensen, Lise K., and Schumacher, M. Catherine
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Insulin -- Receptors ,Branched chain amino acids -- Physiological aspects -- Genetic aspects ,Methionine -- Physiological aspects -- Genetic aspects ,Insulin resistance -- Physiological aspects -- Genetic aspects ,Type 2 diabetes -- Genetic aspects ,Health ,Physiological aspects ,Genetic aspects - Abstract
INSR gene mutations have been described in multiple individuals with extreme insulin resistance, but the INSR gene has not been implicated in familial NIDDM. We previously have screened members of [...]
- Published
- 1993
14. Linkage analysis of insulin-receptor gene in familial NIDDM
- Author
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Elbein, Steven C., Sorensen, Lise K., and Taylor, Michelle
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Insulin -- Receptors ,Linkage (Genetics) -- Research -- Genetic aspects ,Type 2 diabetes -- Genetic aspects -- Research ,Health ,Genetic aspects ,Research - Abstract
Although non-insulin-dependent diabetes mellitus (NIDDM) is clearly inherited, the mode of inheritance and genetic etiology remain unknown. Impaired insulin action is an important component of NIDDM, which may precede NIDDM onset, and appears to be inherited. Numerous defects of the insulin-receptor gene have been described in syndrome of extreme insulin resistance, and this gene is a strong candidate for genetic predisposition to NIDDM. To test this hypothesis, we examined 18 white pedigrees from Utah that had two or more siblings with NIDDM. For each pedigree, individuals not known to be affected were tested by standard oral glucose tolerance test, and diagnoses of NIDDM and impaired glucose tolerance were made by World Health Organization criteria. Each individual was typed for seven restriction-fragment--length polymorphism markets at the insulin-receptor locus, and marker phase was established by segregation. Linkage was examined with the LINKAGE program under six models, including autosomal dominant and autosomal recessive, with individuals with impaired glucose tolerance counted either as affected or of unknown status and with or without sporadic cases of diabetes. Under each model, linkage was significantly rejected. Neither inspection of individual pedigree log of odds scores nor formal tests of heterogeneity suggested a subgroup in which linkage of NIDDM and insulin-receptor gene was likely. In addition, sharing of insulin-receptor gene haplotypes among 108 affected sibling pairs drawn from the pedigrees did not deviate from that expected by chance alone. These data suggest that the insulin-receptor gene locus is unlikely to act as a major locus in the predisposition to NIDDM in most white pedigrees, although we cannot exclude a minor role for this locus under a highly polygenic model or a major role in rare pedigrees. Diabetes 41:648-56, 1992, Familial aggregation and >90% concordance in identical twins strongly implicate a major genetic locus in the etiology of non-insulin-dependent diabetes mellitus (NIDDM; 1). Except for the autosomal dominant maturity-onset diabetes [...]
- Published
- 1992
15. The Small GTPase ARF6 Stimulates β-Catenin Transcriptional Activity During WNT5A-Mediated Melanoma Invasion and Metastasis.
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Grossmann, Allie H., Jae Hyuk Yoo, Clancy, James, Sorensen, Lise K., Sedgwick, Alanna, Zongzhong Tong, Ostanin, Kirill, Rogers, Aaron, Grossmann, Kenneth F., Tripp, Sheryl R., Thomas, Kirk R., D'Souza-Schorey, Crislyn, Odelberg, Shannon J., and Li, Dean Y.
- Published
- 2013
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16. Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and Influenza.
- Author
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London, Nyall R., Weiquan Zhu, Bozza, Fernando A., Smith, Matthew C. P., Greif, Daniel M., Sorensen, Lise K., Chen, Luming, Kaminoh, Yuuki, Chan, Aubrey C., Passi, Samuel F., Day, Craig W., Barnard, Dale L., Zimmerman, Guy A., Krasnow, Mark A., and Li, Dean Y.
- Published
- 2010
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17. Slit2–Robo4 signalling promotes vascular stability by blocking Arf6 activity.
- Author
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Jones, Christopher A., Nishiya, Naoyuki, London, Nyall R., Zhu, Weiquan, Sorensen, Lise K., Chan, Aubrey C., Lim, Chinten J., Chen, Haoyu, Zhang, Qisheng, Schultz, Peter G., Hayallah, Alaa M., Thomas, Kirk R., Famulok, Michael, Zhang, Kang, Ginsberg, Mark H., and Li, Dean Y.
- Subjects
VASCULAR endothelial growth factors ,CARDIOVASCULAR system ,CELL membranes ,AXONS ,NEOVASCULARIZATION ,FIBRONECTINS - Abstract
Slit–Roundabout (Robo) signalling has a well-understood role in axon guidance. Unlike in the nervous system, however, Slit-dependent activation of an endothelial-specific Robo, Robo4, does not initiate a guidance program. Instead, Robo4 maintains the barrier function of the mature vascular network by inhibiting neovascular tuft formation and endothelial hyperpermeability induced by pro-angiogenic factors. In this study, we used cell biological and biochemical techniques to elucidate the molecular mechanism underlying the maintenance of vascular stability by Robo4. Here, we demonstrate that Robo4 mediates Slit2-dependent suppression of cellular protrusive activity through direct interaction with the intracellular adaptor protein paxillin and its paralogue, Hic-5. Formation of a Robo4–paxillin complex at the cell surface blocks activation of the small GTPase Arf6 and, consequently, Rac by recruitment of Arf-GAPs (ADP-ribosylation factor- directed GTPase-activating proteins) such as GIT1. Consistent with these in vitro studies, inhibition of Arf6 activity in vivo phenocopies Robo4 activation by reducing pathologic angiogenesis in choroidal and retinal vascular disease and VEGF-165 (vascular endothelial growth factor-165)-induced retinal hyperpermeability. These data reveal that a Slit2–Robo4–paxillin–GIT1 network inhibits the cellular protrusive activity underlying neovascularization and vascular leak, and identify a new therapeutic target for ameliorating diseases involving the vascular system. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
18. HOXA13 Is Essential for Placental Vascular Patterning and Labyrinth Endothelial Specification.
- Author
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Shaut, Carley A. E., Keene, Douglas R., Sorensen, Lise K., Li, Dean Y., and Stadler, H. Scott
- Abstract
In eutherian mammals, embryonic growth and survival is dependent on the formation of the placenta, an organ that facilitates the efficient exchange of oxygen, nutrients, and metabolic waste between the maternal and fetal blood supplies. Key to the placenta's function is the formation of its vascular labyrinth, a series of finely branched vessels whose molecular ontogeny remains largely undefined. In this report, we demonstrate that HOXA13 plays an essential role in labyrinth vessel formation. In the absence of HOXA13 function, placental endothelial cell morphology is altered, causing a loss in vessel wall integrity, edema of the embryonic blood vessels, and mid-gestational lethality. Microarray analysis of wild-type and mutant placentas revealed significant changes in endothelial gene expression profiles. Notably, pro-vascular genes, including Tie2 and Foxf1, exhibited reduced expression in the mutant endothelia, which also exhibited elevated expression of genes normally expressed in lymphatic or sinusoidal endothelia. ChIP analysis of HOXA13–DNA complexes in the placenta confirmed that HOXA13 binds the Tie2 and Foxf1 promoters in vivo. In vitro, HOXA13 binds sequences present in the Tie2 and Foxf1 promoters with high affinity (K
d = 27–42 nM) and HOXA13 can use these bound promoter regions to direct gene expression. Taken together, these findings demonstrate that HOXA13 directly regulates Tie2 and Foxf1 in the placental labyrinth endothelia, providing a functional explanation for the mid-gestational lethality exhibited by Hoxa13 mutant embryos as well as a novel transcriptional program necessary for the specification of the labyrinth vascular endothelia. [ABSTRACT FROM AUTHOR]- Published
- 2008
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19. Arteriovenous malformations in mice lacking activin receptor-like kinase-1.
- Author
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Urness, Lisa D., Sorensen, Lise K., and Li, Dean Y.
- Subjects
- *
TELANGIECTASIA , *BLOOD-vessel abnormalities , *ACTIVIN , *GENETICS - Abstract
The mature circulatory system is comprised of two parallel, yet distinct, vascular networks that carry blood to and from the heart. Studies have suggested that endothelial tubes are specified as arteries and veins at the earliest stages of angiogenesis, before the onset of circulation. To understand the molecular basis for arterial-venous identity, we have focused our studies on a human vascular dysplasia, hereditary haemorrhagic telangiectasia (HHT), wherein arterial and venous beds fail to remain distinct. Genetic studies have demonstrated that HHT can be caused by loss-of-function mutations in the gene encoding activin receptor-like kinase-1 (ACVRL1; ref. 5). ACVRL1 encodes a type I receptor for the TGF-β superfamily of growth factors. At the earliest stage of vascular development, mice lacking Acvrl1 develop large shunts between arteries and veins, downregulate arterial Efnb2 and fail to confine intravascular haematopoiesis to arteries. These mice die by mid-gestation with severe arteriovenous malformations resulting from fusion of major arteries and veins. The early loss of anatomical, molecular and functional distinctions between arteries and veins indicates that Acvrl1 is required for developing distinct arterial and venous vascular beds. [ABSTRACT FROM AUTHOR]
- Published
- 2000
- Full Text
- View/download PDF
20. Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy.
- Author
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Winter, Jacob M., Rich, Bianca E., Sorensen, Lise K., Helong Zhao, Mleynek, Tara M., Jae Hyuk Yoo, Jing Ling, Bergquist, Jake A., Jiang, Amanda, Thomas, Kirk R., Odelberg, Shannon J., Weiquan Zhu, Li, Dean Y., Shi, Dallas S., Richards, Jackson R., Hartnett, M. Elizabeth, Ward, Diane M., Dunn, Christine, Mueller, Alan L., and Ostanin, Kirill
- Subjects
- *
ADP-ribosylation factors , *VASCULAR endothelial growth factor genetics , *DIABETIC retinopathy , *GUANOSINE triphosphatase genetics , *NEOVASCULARIZATION , *GENETICS of diabetes , *CELLULAR signal transduction , *GENETICS - Abstract
The devastating sequelae of diabetes mellitus include microvascular permeability, which results in retinopathy. Despite clinical and scientific advances, there remains a need for new approaches to treat retinopathy. Here, we have presented a possible treatment strategy, whereby targeting the small GTPase ARF6 alters VEGFR2 trafficking and reverses signs of pathology in 4 animal models that represent features of diabetic retinopathy and in a fifth model of ocular pathological angiogenesis. Specifically, we determined that the same signaling pathway utilizes distinct GEFs to sequentially activate ARF6, and these GEFs exert distinct but complementary effects on VEGFR2 trafficking and signal transduction. ARF6 activation was independently regulated by 2 different ARF GEFs - ARNO and GEP100. Interaction between VEGFR2 and ARNO activated ARF6 and stimulated VEGFR2 internalization, whereas a VEGFR2 interaction with GEP100 activated ARF6 to promote VEGFR2 recycling via coreceptor binding. Intervening in either pathway inhibited VEGFR2 signal output. Finally, using a combination of in vitro, cellular, genetic, and pharmacologic techniques, we demonstrated that ARF6 is pivotal in VEGFR2 trafficking and that targeting ARF6-mediated VEGFR2 trafficking has potential as a therapeutic approach for retinal vascular diseases such as diabetic retinopathy. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
21. The netrin receptor UNC5B promotes angiogenesis in specific vascular beds.
- Author
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Navankasattusas, Sutip, Whitehead, Kevin J., Suli, Arminda, Sorensen, Lise K., Lim, Amy H., Jia Zhao, Kye Won Park, Wythe, Joshua D., Thomas, Kirk R., Chi-Bin Chien, and Li, Dean Y.
- Subjects
NEOVASCULARIZATION ,BLOOD vessels ,PLACENTA ,ZEBRA danio ,LABORATORY mice - Abstract
There is emerging evidence that the canonical neural guidance factor netrin can also direct the growth of blood vessels. We deleted the gene encoding UNC5B, a receptor for the netrin family of guidance molecules, specifically within the embryonic endothelium of mice. The result is a profound structural and functional deficiency in the arterioles of the placental labyrinth, which leads first to flow reversal in the umbilical artery and ultimately to embryonic death. As this is the only detectable site of vascular abnormality in the mutant embryos, and because the phenotype cannot be rescued by a wild-type trophectoderm, we propose that UNC5B-mediated signaling is a specific and autonomous component of fetal-placental angiogenesis. Disruption of UNC5B represents a unique example of a mutation that acts solely within the fetal-placental vasculature and one that faithfully recapitulates the structural and physiological characteristics of clinical uteroplacental insufficiency. This pro-angiogenic, but spatially restricted requirement for UNC5B is not unique to murine development, as the knock-down of the Unc5b ortholog in zebrafish similarly results in the specific and highly penetrant absence of the parachordal vessel, the precursor to the lymphatic system. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
22. Neuroinflammatory disease disrupts the blood-CNS barrier via crosstalk between proinflammatory and endothelial-to-mesenchymal-transition signaling.
- Author
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Sun, Zhonglou, Zhao, Helong, Fang, Daniel, Davis, Chadwick T., Shi, Dallas S., Lei, Kachon, Rich, Bianca E., Winter, Jacob M., Guo, Li, Sorensen, Lise K., Pryor, Robert J., Zhu, Nina, Lu, Samuel, Dickey, Laura L., Doty, Daniel J., Tong, Zongzhong, Thomas, Kirk R., Mueller, Alan L., Grossmann, Allie H., and Zhang, Baowei
- Subjects
- *
NEUROLOGICAL disorders , *NERVOUS system , *MULTIPLE sclerosis , *ADP-ribosylation , *LABORATORY mice , *CENTRAL nervous system viral diseases - Abstract
Breakdown of the blood-central nervous system barrier (BCNSB) is a hallmark of many neuroinflammatory disorders, such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we show that endothelial-to-mesenchymal transition (EndoMT) occurs in the CNS before the onset of clinical symptoms and plays a major role in the breakdown of BCNSB function. EndoMT can be induced by an IL-1β-stimulated signaling pathway in which activation of the small GTPase ADP ribosylation factor 6 (ARF6) leads to crosstalk with the activin receptor-like kinase (ALK)-SMAD1/5 pathway. Inhibiting the activation of ARF6 both prevents and reverses EndoMT, stabilizes BCNSB function, reduces demyelination, and attenuates symptoms even after the establishment of severe EAE, without immunocompromising the host. Pan-inhibition of ALKs also reduces disease severity in the EAE model. Therefore, multiple components of the IL-1β-ARF6-ALK-SMAD1/5 pathway could be targeted for the treatment of a variety of neuroinflammatory disorders. [Display omitted] • EndoMT occurs in the CNS before the onset of symptoms in a mouse model of MS • EndoMT helps drive the loss of BCNSB function and is induced by ARF6 activation • ARF6 activation mediates crosstalk between IL-1β and ALK-SMAD1/5 signaling pathways • Inhibiting the IL-1β-ARF6-ALK-SMAD1/5 pathway reverses EndoMT and disease severity Loss of blood-CNS barrier (BCNSB) function is a hallmark of neuroinflammatory diseases, including MS. Sun et al. show that ARF6-mediated crosstalk between IL-1β and ALK signaling induces presymptomatic endothelial-to-mesenchymal transition (EndoMT), causing BCNSB disruption and disease progression in a mouse MS model. Inhibiting this pathway reverses EndoMT and disease severity, suggesting a new therapeutic strategy to treat MS. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
23. ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma.
- Author
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Yoo, Jae Hyuk, Shi, Dallas S., Grossmann, Allie H., Sorensen, Lise K., Tong, ZongZhong, Mleynek, Tara M., Rogers, Aaron, Zhu, Weiquan, Richards, Jackson R., Winter, Jacob M., Zhu, Jie, Dunn, Christine, Bajji, Ashok, Shenderovich, Mark, Mueller, Alan L., Woodman, Scott E., Harbour, J. William, Thomas, Kirk R., Odelberg, Shannon J., and Ostanin, Kirill
- Subjects
- *
UVEA cancer , *G proteins , *ADP-ribosylation factors , *CANCER cell proliferation , *NEOPLASTIC cell transformation - Abstract
Summary Activating mutations in Gαq proteins, which form the α subunit of certain heterotrimeric G proteins, drive uveal melanoma oncogenesis by triggering multiple downstream signaling pathways, including PLC/PKC, Rho/Rac, and YAP. Here we show that the small GTPase ARF6 acts as a proximal node of oncogenic Gαq signaling to induce all of these downstream pathways as well as β-catenin signaling. ARF6 activates these diverse pathways through a common mechanism: the trafficking of GNAQ and β-catenin from the plasma membrane to cytoplasmic vesicles and the nucleus, respectively. Blocking ARF6 with a small-molecule inhibitor reduces uveal melanoma cell proliferation and tumorigenesis in a mouse model, confirming the functional relevance of this pathway and suggesting a therapeutic strategy for Gα-mediated diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
24. The Small GTPase ARF6 Activates PI3K in Melanoma to Induce a Prometastatic State.
- Author
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Yoo JH, Brady SW, Acosta-Alvarez L, Rogers A, Peng J, Sorensen LK, Wolff RK, Mleynek T, Shin D, Rich CP, Kircher DA, Bild A, Odelberg SJ, Li DY, Holmen SL, and Grossmann AH
- Subjects
- ADP-Ribosylation Factor 6, ADP-Ribosylation Factors genetics, Animals, Cyclin-Dependent Kinase Inhibitor p16 genetics, Guanosine Triphosphate metabolism, Humans, Lung Neoplasms secondary, Melanoma metabolism, Melanoma, Experimental metabolism, Melanoma, Experimental pathology, Mice, Mutant Strains, Mice, SCID, Neoplasm Metastasis, PTEN Phosphohydrolase genetics, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins c-akt metabolism, Skin Neoplasms metabolism, ADP-Ribosylation Factors metabolism, Melanoma pathology, Phosphatidylinositol 3-Kinases metabolism, Skin Neoplasms pathology
- Abstract
Melanoma has an unusual capacity to spread in early-stage disease, prompting aggressive clinical intervention in very thin primary tumors. Despite these proactive efforts, patients with low-risk, low-stage disease can still develop metastasis, indicating the presence of permissive cues for distant spread. Here, we show that constitutive activation of the small GTPase ARF6 (ARF6
Q67L ) is sufficient to accelerate metastasis in mice with BRAFV600E /Cdkn2aNULL melanoma at a similar incidence and severity to Pten loss, a major driver of PI3K activation and melanoma metastasis. ARF6Q67L promoted spontaneous metastasis from significantly smaller primary tumors than PTENNULL , implying an enhanced ability of ARF6-GTP to drive distant spread. ARF6 activation increased lung colonization from circulating melanoma cells, suggesting that the prometastatic function of ARF6 extends to late steps in metastasis. Unexpectedly, ARF6Q67L tumors showed upregulation of Pik3r1 expression, which encodes the p85 regulatory subunit of PI3K. Tumor cells expressing ARF6Q67L displayed increased PI3K protein levels and activity, enhanced PI3K distribution to cellular protrusions, and increased AKT activation in invadopodia. ARF6 is necessary and sufficient for activation of both PI3K and AKT, and PI3K and AKT are necessary for ARF6-mediated invasion. We provide evidence for aberrant ARF6 activation in human melanoma samples, which is associated with reduced survival. Our work reveals a previously unknown ARF6-PI3K-AKT proinvasive pathway, it demonstrates a critical role for ARF6 in multiple steps of the metastatic cascade, and it illuminates how melanoma cells can acquire an early metastatic phenotype in patients. SIGNIFICANCE: These findings reveal a prometastatic role for ARF6 independent of tumor growth, which may help explain how melanoma spreads distantly from thin, early-stage primary tumors. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/11/2892/F1.large.jpg., (©2019 American Association for Cancer Research.)- Published
- 2019
- Full Text
- View/download PDF
25. Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.
- Author
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Schell JC, Wisidagama DR, Bensard C, Zhao H, Wei P, Tanner J, Flores A, Mohlman J, Sorensen LK, Earl CS, Olson KA, Miao R, Waller TC, Delker D, Kanth P, Jiang L, DeBerardinis RJ, Bronner MP, Li DY, Cox JE, Christofk HR, Lowry WE, Thummel CS, and Rutter J
- Subjects
- Acrylates pharmacology, Animals, Anion Transport Proteins antagonists & inhibitors, Anion Transport Proteins genetics, Anion Transport Proteins metabolism, Cell Differentiation, Cells, Cultured, Drosophila Proteins genetics, Drosophila Proteins metabolism, Drosophila melanogaster cytology, Genotype, Humans, Intestines cytology, Intestines drug effects, Lactic Acid metabolism, Mice, Knockout, Mitochondria drug effects, Mitochondrial Membrane Transport Proteins antagonists & inhibitors, Mitochondrial Membrane Transport Proteins genetics, Mitochondrial Membrane Transport Proteins metabolism, Mitochondrial Proteins metabolism, Monocarboxylic Acid Transporters, Phenotype, RNA Interference, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Signal Transduction, Stem Cells drug effects, Time Factors, Tissue Culture Techniques, Transfection, Cell Proliferation drug effects, Drosophila melanogaster metabolism, Glycolysis, Intestinal Mucosa metabolism, Mitochondria metabolism, Pyruvic Acid metabolism, Stem Cells metabolism
- Abstract
Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells.
- Published
- 2017
- Full Text
- View/download PDF
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