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1. Supplementary Figures from MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Author

Sakthianandeswaren, Anuratha, primary, Parsons, Marie J., primary, Mouradov, Dmitri, primary, MacKinnon, Ruth N., primary, Catimel, Bruno, primary, Liu, Sheng, primary, Palmieri, Michelle, primary, Love, Christopher, primary, Jorissen, Robert N., primary, Li, Shan, primary, Whitehead, Lachlan, primary, Putoczki, Tracy L., primary, Preaudet, Adele, primary, Tsui, Cary, primary, Nowell, Cameron J., primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Desai, Jayesh, primary, Gibbs, Peter, primary, Ernst, Matthias, primary, Street, Ian, primary, Buchert, Michael, primary, and Sieber, Oliver M., primary

Published
2024
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2. Supplementary Tables from MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Author

Sakthianandeswaren, Anuratha, primary, Parsons, Marie J., primary, Mouradov, Dmitri, primary, MacKinnon, Ruth N., primary, Catimel, Bruno, primary, Liu, Sheng, primary, Palmieri, Michelle, primary, Love, Christopher, primary, Jorissen, Robert N., primary, Li, Shan, primary, Whitehead, Lachlan, primary, Putoczki, Tracy L., primary, Preaudet, Adele, primary, Tsui, Cary, primary, Nowell, Cameron J., primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Desai, Jayesh, primary, Gibbs, Peter, primary, Ernst, Matthias, primary, Street, Ian, primary, Buchert, Michael, primary, and Sieber, Oliver M., primary

Published
2023
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3. Supplementary Data from MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Author

Sakthianandeswaren, Anuratha, primary, Parsons, Marie J., primary, Mouradov, Dmitri, primary, MacKinnon, Ruth N., primary, Catimel, Bruno, primary, Liu, Sheng, primary, Palmieri, Michelle, primary, Love, Christopher, primary, Jorissen, Robert N., primary, Li, Shan, primary, Whitehead, Lachlan, primary, Putoczki, Tracy L., primary, Preaudet, Adele, primary, Tsui, Cary, primary, Nowell, Cameron J., primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Desai, Jayesh, primary, Gibbs, Peter, primary, Ernst, Matthias, primary, Street, Ian, primary, Buchert, Michael, primary, and Sieber, Oliver M., primary

Published
2023
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4. Data from MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Author

Sakthianandeswaren, Anuratha, primary, Parsons, Marie J., primary, Mouradov, Dmitri, primary, MacKinnon, Ruth N., primary, Catimel, Bruno, primary, Liu, Sheng, primary, Palmieri, Michelle, primary, Love, Christopher, primary, Jorissen, Robert N., primary, Li, Shan, primary, Whitehead, Lachlan, primary, Putoczki, Tracy L., primary, Preaudet, Adele, primary, Tsui, Cary, primary, Nowell, Cameron J., primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Desai, Jayesh, primary, Gibbs, Peter, primary, Ernst, Matthias, primary, Street, Ian, primary, Buchert, Michael, primary, and Sieber, Oliver M., primary

Published
2023
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5. Supplementary Methods from MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Author

Sakthianandeswaren, Anuratha, primary, Parsons, Marie J., primary, Mouradov, Dmitri, primary, MacKinnon, Ruth N., primary, Catimel, Bruno, primary, Liu, Sheng, primary, Palmieri, Michelle, primary, Love, Christopher, primary, Jorissen, Robert N., primary, Li, Shan, primary, Whitehead, Lachlan, primary, Putoczki, Tracy L., primary, Preaudet, Adele, primary, Tsui, Cary, primary, Nowell, Cameron J., primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Desai, Jayesh, primary, Gibbs, Peter, primary, Ernst, Matthias, primary, Street, Ian, primary, Buchert, Michael, primary, and Sieber, Oliver M., primary

Published
2023
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6. Supplementary Figures from MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Author

Sakthianandeswaren, Anuratha, primary, Parsons, Marie J., primary, Mouradov, Dmitri, primary, MacKinnon, Ruth N., primary, Catimel, Bruno, primary, Liu, Sheng, primary, Palmieri, Michelle, primary, Love, Christopher, primary, Jorissen, Robert N., primary, Li, Shan, primary, Whitehead, Lachlan, primary, Putoczki, Tracy L., primary, Preaudet, Adele, primary, Tsui, Cary, primary, Nowell, Cameron J., primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Desai, Jayesh, primary, Gibbs, Peter, primary, Ernst, Matthias, primary, Street, Ian, primary, Buchert, Michael, primary, and Sieber, Oliver M., primary

Published
2023
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7. PI3Kα Translocation Mediates Nuclear PtdIns(3,4,5)P3 Effector Signaling in Colorectal Cancer

Author

Palmieri, Michelle, primary, Catimel, Bruno, additional, Mouradov, Dmitri, additional, Sakthianandeswaren, Anuratha, additional, Kapp, Eugene, additional, Ang, Ching-Seng, additional, Williamson, Nicholas A., additional, Nowell, Cameron J., additional, Christie, Michael, additional, Desai, Jayesh, additional, Gibbs, Peter, additional, Burgess, Antony W., additional, and Sieber, Oliver M., additional

Published
2023
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9. Data from PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

Author

Sakthianandeswaren, Anuratha, primary, Christie, Michael, primary, D'Andreti, Carla, primary, Tsui, Cary, primary, Jorissen, Robert N., primary, Li, Shan, primary, Fleming, Nicholas I., primary, Gibbs, Peter, primary, Lipton, Lara, primary, Malaterre, Jordane, primary, Ramsay, Robert G., primary, Phesse, Toby J., primary, Ernst, Matthias, primary, Jeffery, Rosemary E., primary, Poulsom, Richard, primary, Leedham, Simon J., primary, Segditsas, Stefania, primary, Tomlinson, Ian P. M., primary, Bernhard, Oliver K., primary, Simpson, Richard J., primary, Walker, Francesca, primary, Faux, Maree C., primary, Church, Nicole, primary, Catimel, Bruno, primary, Flanagan, Dustin J., primary, Vincan, Elizabeth, primary, and Sieber, Oliver M., primary

Published
2023
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10. Supplementary Methods and Materials from PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

Author

Sakthianandeswaren, Anuratha, primary, Christie, Michael, primary, D'Andreti, Carla, primary, Tsui, Cary, primary, Jorissen, Robert N., primary, Li, Shan, primary, Fleming, Nicholas I., primary, Gibbs, Peter, primary, Lipton, Lara, primary, Malaterre, Jordane, primary, Ramsay, Robert G., primary, Phesse, Toby J., primary, Ernst, Matthias, primary, Jeffery, Rosemary E., primary, Poulsom, Richard, primary, Leedham, Simon J., primary, Segditsas, Stefania, primary, Tomlinson, Ian P. M., primary, Bernhard, Oliver K., primary, Simpson, Richard J., primary, Walker, Francesca, primary, Faux, Maree C., primary, Church, Nicole, primary, Catimel, Bruno, primary, Flanagan, Dustin J., primary, Vincan, Elizabeth, primary, and Sieber, Oliver M., primary

Published
2023
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11. Supplementary Figures 1-3 from PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

Author

Sakthianandeswaren, Anuratha, primary, Christie, Michael, primary, D'Andreti, Carla, primary, Tsui, Cary, primary, Jorissen, Robert N., primary, Li, Shan, primary, Fleming, Nicholas I., primary, Gibbs, Peter, primary, Lipton, Lara, primary, Malaterre, Jordane, primary, Ramsay, Robert G., primary, Phesse, Toby J., primary, Ernst, Matthias, primary, Jeffery, Rosemary E., primary, Poulsom, Richard, primary, Leedham, Simon J., primary, Segditsas, Stefania, primary, Tomlinson, Ian P. M., primary, Bernhard, Oliver K., primary, Simpson, Richard J., primary, Walker, Francesca, primary, Faux, Maree C., primary, Church, Nicole, primary, Catimel, Bruno, primary, Flanagan, Dustin J., primary, Vincan, Elizabeth, primary, and Sieber, Oliver M., primary

Published
2023
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12. Supplementary Tables 1-2 from PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

Author

Sakthianandeswaren, Anuratha, primary, Christie, Michael, primary, D'Andreti, Carla, primary, Tsui, Cary, primary, Jorissen, Robert N., primary, Li, Shan, primary, Fleming, Nicholas I., primary, Gibbs, Peter, primary, Lipton, Lara, primary, Malaterre, Jordane, primary, Ramsay, Robert G., primary, Phesse, Toby J., primary, Ernst, Matthias, primary, Jeffery, Rosemary E., primary, Poulsom, Richard, primary, Leedham, Simon J., primary, Segditsas, Stefania, primary, Tomlinson, Ian P. M., primary, Bernhard, Oliver K., primary, Simpson, Richard J., primary, Walker, Francesca, primary, Faux, Maree C., primary, Church, Nicole, primary, Catimel, Bruno, primary, Flanagan, Dustin J., primary, Vincan, Elizabeth, primary, and Sieber, Oliver M., primary

Published
2023
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20. Antibodies Specifically Targeting a Locally Misfolded Region of Tumor Associated EGFR

Author

Garrett, Thomas P. J., Burgess, Antony W., Gan, Hui K., Luwor, Rod B., Cartwright, Glenn, Walker, Francesca, Orchard, Suzanne G., Clayton, Andrew H. A., Nice, Edouard C., Rothacker, Julie, Catimel, Bruno, Cavenee, Webster K., Old, Lloyd J., Stockert, Elisabeth, Ritter, Gerd, Adams, Timothy E., Hoyne, Peter A., Wittrup, Dane, Chao, Ginger, Cochran, Jennifer R., Luo, Cindy, Lou, Mezhen, Huyton, Trevor, Xu, Yibin, Fairlie, W. Douglas, Yao, Shenggen, Scott, Andrew M., Johns, Terrance G., and Adams, Jerry M.

Published
2009
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22. mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice

Author

Thiem, Stefan, Pierce, Thomas P., Palmieri, Michelle, Putoczki, Tracy L., Buchert, Michael, Preaudet, Adele, Farid, Ryan O., Love, Chris, Catimel, Bruno, Lei, Zhengdeng, Rozen, Steve, Gopalakrishnan, Veena, Schaper, Fred, Hallek, Michael, Boussioutas, Alex, Tan, Patrick, Jarnicki, Andrew, and Ernst, Matthias

Subjects
Cytokines -- Health aspects -- Physiological aspects -- Research, Gastrointestinal tumors -- Risk factors -- Research -- Development and progression -- Genetic aspects, Health care industry
Abstract

Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of Stat3 in mice, this transcription factor remains a challenging therapeutic target with a paucity of clinically approved inhibitors. Here, we uncovered parallel and excessive activation of mTOR complex 1 (mTORC1) alongside STAT3 in human intestinal-type gastric cancers (IGCs). Furthermore, in a preclinical mouse model of IGC, GP130 ligand administration simultaneously activated mTORC1/S6 kinase and STAT3 signaling. We therefore investigated whether mTORC1 activation was required for inflammation-associated gastrointestinal tumorigenesis. Strikingly, the mTORC1-specific inhibitor RAD001 potently suppressed initiation and progression of both murine IGC and colitis-associated colon cancer. The therapeutic effect of RAD001 was associated with reduced tumor vascularization and cell proliferation but occurred independently of STAT3 activity. We analyzed the mechanism of GP130-mediated mTORC1 activation in cells and mice and revealed a requirement for JAK and PI3K activity but not for GP130 tyrosine phosphorylation or STAT3. Our results suggest that GP130-dependent activation of the druggable PI3K/mTORC1 pathway is required for inflammation-associated gastrointestinal tumorigenesis. These findings advocate clinical application of PI3K/mTORC1 inhibitors for the treatment of corresponding human malignancies., Introduction During the multistep process of tumor formation conditions within the tissue microenvironment can influence the fate of premalignant cells. In inflammation-associated cancers, tumor promotion is thought to be facilitated [...]

Published
2013
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28. c-Raf-1 RBD associates with a subset of active v-H-Ras

Author

Fridman, Masha, Walker, Francesca, Catimel, Bruno, Domagala, Teresa, Nice, Edourad, and Burgess, Antony

Subjects
Ras genes -- Physiological aspects, Ligand binding (Biochemistry) -- Analysis, Gene mutations -- Analysis, Cellular signal transduction -- Physiological aspects, Biological sciences, Chemistry
Abstract

Results demonstrate that Ras proteins exist in distinct Ras/GTP isoforms and only few of them can bind to wild-type Ras binding domain. Data indicate that cRaf-1 Ras binding domain exhibits elelvated Ras binding, much of it belonging to v-H-Ras type of binding domain.

Published
2000

34. A Mechanism for Actin Filament Severing by Malaria Parasite Actin Depolymerizing Factor 1 via a Low Affinity Binding Interface*

Author

Wong, Wilson, Webb, Andrew I., Olshina, Maya A., Infusini, Giuseppe, Tan, Yan Hong, Hanssen, Eric, Catimel, Bruno, Suarez, Cristian, Condron, Melanie, Angrisano, Fiona, NebI, Thomas, Kovar, David R., and Baum, Jake

Subjects
Cofilin 1, Plasmodium, Binding Sites, Cytochalasin D, musculoskeletal, neural, and ocular physiology, Plasmodium falciparum, Protozoan Proteins, macromolecular substances, Actins, Malaria, Actin Cytoskeleton, Destrin, nervous system, Protein Cross-linking, Mass Spectrometry (MS), Cofilin, Protein Structure and Folding, Humans, Electron Microscopy (EM), Actin, Cytoskeleton
Abstract

Background: Plasmodium falciparum actin depolymerizing factor 1 (PfADF1) severs actin polymers without stable filament-binding, challenging current models for severing. Results: Cross-linking mass spectrometry of PfADF1 with filamentous actin reveals a novel binding interface required for severing. Conclusion: Filament severing by PfADF1 is via a previously unidentified binding interface. Significance: We propose an alternative mechanism for actin filament severing potentially used across eukaryotic cells., Actin depolymerizing factor (ADF)/cofilins are essential regulators of actin turnover in eukaryotic cells. These multifunctional proteins facilitate both stabilization and severing of filamentous (F)-actin in a concentration-dependent manner. At high concentrations ADF/cofilins bind stably to F-actin longitudinally between two adjacent actin protomers forming what is called a decorative interaction. Low densities of ADF/cofilins, in contrast, result in the optimal severing of the filament. To date, how these two contrasting modalities are achieved by the same protein remains uncertain. Here, we define the proximate amino acids between the actin filament and the malaria parasite ADF/cofilin, PfADF1 from Plasmodium falciparum. PfADF1 is unique among ADF/cofilins in being able to sever F-actin but do so without stable filament binding. Using chemical cross-linking and mass spectrometry (XL-MS) combined with structure reconstruction we describe a previously overlooked binding interface on the actin filament targeted by PfADF1. This site is distinct from the known binding site that defines decoration. Furthermore, total internal reflection fluorescence (TIRF) microscopy imaging of single actin filaments confirms that this novel low affinity site is required for F-actin severing. Exploring beyond malaria parasites, selective blocking of the decoration site with human cofilin (HsCOF1) using cytochalasin D increases its severing rate. HsCOF1 may therefore also use a decoration-independent site for filament severing. Thus our data suggest that a second, low affinity actin-binding site may be universally used by ADF/cofilins for actin filament severing.

Published
2013

35. MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Author

Sakthianandeswaren, Anuratha, primary, Parsons, Marie J., additional, Mouradov, Dmitri, additional, MacKinnon, Ruth N., additional, Catimel, Bruno, additional, Liu, Sheng, additional, Palmieri, Michelle, additional, Love, Christopher, additional, Jorissen, Robert N., additional, Li, Shan, additional, Whitehead, Lachlan, additional, Putoczki, Tracy L., additional, Preaudet, Adele, additional, Tsui, Cary, additional, Nowell, Cameron J., additional, Ward, Robyn L., additional, Hawkins, Nicholas J., additional, Desai, Jayesh, additional, Gibbs, Peter, additional, Ernst, Matthias, additional, Street, Ian, additional, Buchert, Michael, additional, and Sieber, Oliver M., additional

Published
2018
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36. Development of monoclonal anti-PDGF-CC antibodies as tools for investigating human tissue expression and for blocking PDGF-CC induced PDGFRα signalling in vivo

Author

Li, Hong, primary, Zeitelhofer, Manuel, additional, Nilsson, Ingrid, additional, Liu, Xicong, additional, Allan, Laura, additional, Gloria, Benjamin, additional, Perani, Angelo, additional, Murone, Carmel, additional, Catimel, Bruno, additional, Neville, A. Munro, additional, Scott, Fiona E., additional, Scott, Andrew M., additional, and Eriksson, Ulf, additional

Published
2018
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37. Csk-homologous kinase (Chk) is an efficient inhibitor of Src-family kinases but a poor catalyst of phosphorylation of their C-terminal regulatory tyrosine

Author

Advani, Gahana, primary, Lim, Ya Chee, additional, Catimel, Bruno, additional, Lio, Daisy Sio Seng, additional, Ng, Nadia L. Y., additional, Chüeh, Anderly C., additional, Tran, Mai, additional, Anasir, Mohd Ishtiaq, additional, Verkade, Heather, additional, Zhu, Hong-Jian, additional, Turk, Benjamin E., additional, Smithgall, Thomas E., additional, Ang, Ching-Seng, additional, Griffin, Michael, additional, and Cheng, Heung-Chin, additional

Published
2017
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38. Characterization of mouse A33 antigen, a definitive marker for basolateral surfaces of intestinal epithelial cells

Author

JOHNSTONE, CAMERON N., TEBBUTT, NIALL C., ABUD, HELEN E., WHITE, SARA J., STENVERS, KAYE L., HALL, NATHAN E., CODY, STEPHEN H., WHITEHEAD, ROBERT H., CATIMEL, BRUNO, NICE, EDOUARD C., BURGESS, ANTONY W., and HEATH, JOAN K.

Subjects
Physiology -- Research, Immunoglobulins -- Research, Intestines -- Research, Biological sciences
Abstract

Characterization of mouse A33 antigen, a definitive marker for basolateral surfaces of intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 279: G500-G510, 2000.--The murine A33 antigen is emerging as a definitive marker of intestinal epithelial cells. Cloning and sequence determination of cDNAs encoding mA33 antigen predict a novel type 1 transmembrane protein of 298 amino acids, comprising an extracellular domain with two immunoglobulin-like domains, a single-span transmembrane domain, and a highly acidic cytoplasmic domain. On the basis of conservation of amino acid sequence and genomic structure, the mA33 antigen is a member of a growing subfamily within the immunoglobulin superfamily, which includes transmembrane proteins CTX/ChT1, CTM/CTH, and CAR. During embryonic development, mA33 antigen expression is first observed in the inner cell mass of blastocysts before implantation. Intestinal expression of mA33 antigen is initiated in the hindgut at E14.5 and increases steadily throughout late embryonic and postnatal life into adulthood. The protein is specifically expressed on the basolateral surfacers of intestinal epithelial cells of all lineages, independent of their position along the rostrocaudal and crypt-villus axes. Thus the mA33 antigen appears to be a novel marker for both proliferating and differentiating intestinal epithelial cells. immunoglobulin superfamily; intestinal epithelium

Published
2000

39. Cross-species analysis of Fc engineered anti-Lewis-Y human IgG1 variants in human neonatal receptor transgenic mice reveal importance of S254 and Y436 in binding human neonatal Fc receptor

Author

Burvenich, Ingrid J. G., primary, Farrugia, William, additional, Lee, Fook T., additional, Catimel, Bruno, additional, Liu, Zhanqi, additional, Makris, Dahna, additional, Cao, Diana, additional, O'Keefe, Graeme J., additional, Brechbiel, Martin W., additional, King, Dylan, additional, Spirkoska, Violeta, additional, Allan, Laura C., additional, Ramsland, Paul A., additional, and Scott, Andrew M., additional

Published
2016
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43. Plasmodium falciparum coronin organizes arrays of parallel actin filaments potentially guiding directional motility in invasive malaria parasites

Author

Olshina, Maya A, primary, Angrisano, Fiona, additional, Marapana, Danushka S, additional, Riglar, David T, additional, Bane, Kartik, additional, Wong, Wilson, additional, Catimel, Bruno, additional, Yin, Meng-Xin, additional, Holmes, Andrew B, additional, Frischknecht, Friedrich, additional, Kovar, David R, additional, and Baum, Jake, additional

Published
2015
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45. A Mechanism for Actin Filament Severing by Malaria Parasite Actin Depolymerizing Factor 1 via a Low Affinity Binding Interface

Author

Wong, Wilson, primary, Webb, Andrew I., additional, Olshina, Maya A., additional, Infusini, Giuseppe, additional, Tan, Yan Hong, additional, Hanssen, Eric, additional, Catimel, Bruno, additional, Suarez, Cristian, additional, Condron, Melanie, additional, Angrisano, Fiona, additional, NebI, Thomas, additional, Kovar, David R., additional, and Baum, Jake, additional

Published
2014
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48. Synthesis of a Tethered myo-Inositol (1,3,4,5,6)Pentakisphosphate (IP5) Derivative as a Probe for Biological Studies.

Author

Gregory, Mark, Catimel, Bruno, Meng-Xin Yin, Condron, Melanie, Burgess, Antony W., and Holmes, Andrew B.

Subjects
*CHEMICAL synthesis, *INOSITOL phosphates, *AMINE synthesis, *SURFACE plasmon resonance, *PROTEIN kinase B
Abstract

There is sufficient evidence to suggest that myo-inositol pentakisphosphate is a vital intermediate species in higher inositol phosphate metabolism, however, its biological roles and physiological function in cells remain uncertain. A tethered myo-inositol pentakisphosphate (IP5) derivative with a terminal amine group is synthesised allowing facilitated immobilisation onto M-270 magnetic Dynabeads for pull-down experiments and biosensor chip preparation for surface plasmon resonance studies. The probes are validated by both pull-down and surface plasmon resonance (SPR) studies of the known binding protein GRP-1 (general receptor for phosphoinositides 1), and furthermore by SPR studies of protein kinase B (PKB or AKT) binding. [ABSTRACT FROM AUTHOR]

Published
2016
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49. Ligand binding induces a conformational change in epidermal growth factor receptor dimers

Author

Walker, Francesca, primary, Rothacker, Julie, additional, Henderson, Christine, additional, Nice, Edouard C., additional, Catimel, Bruno, additional, Zhang, Hui-Hua, additional, Scott, Andrew M., additional, Bailey, Michael F., additional, Orchard, Suzanne G., additional, Adams, Timothy E., additional, Liu, Zhanqi, additional, Garrett, Thomas P.J., additional, Clayton, Andrew H.A., additional, and Burgess, Antony W., additional

Published
2012
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50. PI3K-alpha translocation mediates nuclear PtdIns(3,4,5)P3effector signaling in colorectal cancer

Author

Palmieri, Michelle, Catimel, Bruno, Mouradov, Dmitri, Sakthianandeswaren, Anuratha, Kapp, Eugene, Ang, Ching-Seng, Williamson, Nicholas A., Nowell, Cameron J, Christie, Michael, Desai, Jayesh, Gibbs, Peter, Burgess, Antony W., and Sieber, Oliver M.

Abstract

The canonical view of phosphatidylinositol 3-kinase alpha (PI3Kα) signaling describes PtdIns(3,4,5)P3generation and activation of downstream effectors at the plasma membrane or at microtubule-bound endosomes. Here, we show that colorectal cancer (CRC) cell lines exhibit a diverse plasma membrane-nuclear distribution of PI3Kα, controlling corresponding levels of subcellular PtdIns(3,4,5)P3pools. PI3Kα nuclear translocation was mediated by the importin β-dependent nuclear import pathway. By PtdIns(3,4,5)P3affinity capture mass spectrometry done in the presence of SDS on CRC cell lines with PI3Kα nuclear localization, we identified 867 potential nuclear PtdIns(3,4,5)P3effector proteins. Nuclear PtdIns(3,4,5)P3interactome proteins were characterized by non-canonical PtdIns(3,4,5)P3binding domains and showed overrepresentation for nuclear membrane, nucleolus and nuclear speckles. The nuclear PtdIns(3,4,5)P3interactome was enriched for proteins related to RNA metabolism, with splicing reporter assays and SC-35 foci staining suggesting a role of EGF-stimulated nuclear PI3Kα signaling in modulating pre-mRNA splicing. In patient tumors, nuclear p110α staining was associated with lower T stage and mucinous histology. These results indicate that PI3Kα translocation mediates nuclear PtdIns(3,4,5)P3effector signaling in human CRC, modulating signaling responses.

Published
2023
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