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SRChing for the substrates of Src.
Reynolds AB, Kanner SB, Bouton AH, Schaller MD, Weed SA, Flynn DC, Parsons JT
(2014) Oncogene 33: 4537-47
MeSH Terms: Animals, Catenins, Cell Transformation, Neoplastic, Cortactin, Crk-Associated Substrate Protein, Focal Adhesion Kinase 1, Gene Expression Regulation, Neoplastic, Humans, Mice, Microfilament Proteins, Neoplasms, Phosphorylation, Proteome, src-Family Kinases
Show Abstract · Added March 28, 2014
By the mid 1980's, it was clear that the transforming activity of oncogenic Src was linked to the activity of its tyrosine kinase domain and attention turned to identifying substrates, the putative next level of control in the pathway to transformation. Among the first to recognize the potential of phosphotyrosine-specific antibodies, Parsons and colleagues launched a risky shotgun-based approach that led ultimately to the cDNA cloning and functional characterization of many of today's best-known Src substrates (for example, p85-Cortactin, p110-AFAP1, p130Cas, p125FAK and p120-catenin). Two decades and over 6000 citations later, the original goals of the project may be seen as secondary to the enormous impact of these protein substrates in many areas of biology. At the request of the editors, this review is not restricted to the current status of the substrates, but reflects also on the anatomy of the project itself and some of the challenges and decisions encountered along the way.
1 Communities
1 Members
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14 MeSH Terms
Crk1/2-dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease.
George B, Verma R, Soofi AA, Garg P, Zhang J, Park TJ, Giardino L, Ryzhova L, Johnstone DB, Wong H, Nihalani D, Salant DJ, Hanks SK, Curran T, Rastaldi MP, Holzman LB
(2012) J Clin Invest 122: 674-92
MeSH Terms: Adolescent, Adult, Aged, Animals, Cell Line, Crk-Associated Substrate Protein, Female, Focal Adhesion Protein-Tyrosine Kinases, Humans, Kidney Diseases, Kidney Glomerulus, Membrane Proteins, Mice, Mice, Knockout, Middle Aged, Phosphatidylinositol 3-Kinases, Podocytes, Proto-Oncogene Proteins c-crk, Pseudopodia, Rats, Rats, Sprague-Dawley, Recombinant Fusion Proteins, Signal Transduction, Young Adult
Show Abstract · Added January 20, 2015
The morphology of healthy podocyte foot processes is necessary for maintaining the characteristics of the kidney filtration barrier. In most forms of glomerular disease, abnormal filter barrier function results when podocytes undergo foot process spreading and retraction by remodeling their cytoskeletal architecture and intercellular junctions during a process known as effacement. The cell adhesion protein nephrin is necessary for establishing the morphology of the kidney podocyte in development by transducing from the specialized podocyte intercellular junction phosphorylation-mediated signals that regulate cytoskeletal dynamics. The present studies extend our understanding of nephrin function by showing that nephrin activation in cultured podocytes induced actin dynamics necessary for lamellipodial protrusion. This process required a PI3K-, Cas-, and Crk1/2-dependent signaling mechanism distinct from the previously described nephrin-Nck1/2 pathway necessary for assembly and polymerization of actin filaments. Our present findings also support the hypothesis that mechanisms governing lamellipodial protrusion in culture are similar to those used in vivo during foot process effacement in a subset of glomerular diseases. In mice, podocyte-specific deletion of Crk1/2 prevented foot process effacement in one model of podocyte injury and attenuated foot process effacement and associated proteinuria in a delayed fashion in a second model. In humans, focal adhesion kinase and Cas phosphorylation - markers of focal adhesion complex-mediated Crk-dependent signaling - was induced in minimal change disease and membranous nephropathy, but not focal segmental glomerulosclerosis. Together, these observations suggest that activation of a Cas-Crk1/2-dependent complex is necessary for foot process effacement observed in distinct subsets of human glomerular diseases.
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24 MeSH Terms
Tyrosine phosphorylation within the SH3 domain regulates CAS subcellular localization, cell migration, and invasiveness.
Janoštiak R, Tolde O, Brůhová Z, Novotný M, Hanks SK, Rösel D, Brábek J
(2011) Mol Biol Cell 22: 4256-67
MeSH Terms: Animals, Cell Adhesion Molecules, Cell Line, Transformed, Cell Line, Tumor, Cell Movement, Cell Transformation, Neoplastic, Crk-Associated Substrate Protein, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesions, Green Fluorescent Proteins, Humans, Mice, Mutation, Neoplasm Invasiveness, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 12, Signal Transduction, Tyrosine, src Homology Domains
Show Abstract · Added January 20, 2015
Crk-associated substrate (CAS) is a major tyrosine-phosphorylated protein in cells transformed by v-crk and v-src oncogenes and plays an important role in invasiveness of Src-transformed cells. A novel phosphorylation site on CAS, Tyr-12 (Y12) within the ligand-binding hydrophobic pocket of the CAS SH3 domain, was identified and found to be enriched in Src-transformed cells and invasive human carcinoma cells. To study the biological significance of CAS Y12 phosphorylation, phosphomimicking Y12E and nonphosphorylatable Y12F mutants of CAS were studied. The phosphomimicking mutation decreased interaction of the CAS SH3 domain with focal adhesion kinase (FAK) and PTP-PEST and reduced tyrosine phosphorylation of FAK. Live-cell imaging showed that green fluorescent protein-tagged CAS Y12E mutant is, in contrast to wild-type or Y12F CAS, excluded from focal adhesions but retains its localization to podosome-type adhesions. Expression of CAS-Y12F in cas-/- mouse embryonic fibroblasts resulted in hyperphosphorylation of the CAS substrate domain, and this was associated with slower turnover of focal adhesions and decreased cell migration. Moreover, expression of CAS Y12F in Src-transformed cells greatly decreased invasiveness when compared to wild-type CAS expression. These findings reveal an important role of CAS Y12 phosphorylation in the regulation of focal adhesion assembly, cell migration, and invasiveness of Src-transformed cells.
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19 MeSH Terms
P130Cas Src-binding and substrate domains have distinct roles in sustaining focal adhesion disassembly and promoting cell migration.
Meenderink LM, Ryzhova LM, Donato DM, Gochberg DF, Kaverina I, Hanks SK
(2010) PLoS One 5: e13412
MeSH Terms: Animals, Cell Movement, Crk-Associated Substrate Protein, Focal Adhesions, Mice, Mice, Knockout, Phosphorylation, Signal Transduction, Substrate Specificity, Tyrosine, src-Family Kinases
Show Abstract · Added December 10, 2013
The docking protein p130Cas is a prominent Src substrate found in focal adhesions (FAs) and is implicated in regulating critical aspects of cell motility including FA disassembly and protrusion of the leading edge plasma membrane. To better understand how p130Cas acts to promote these events we examined requirements for established p130Cas signaling motifs including the SH3-binding site of the Src binding domain (SBD) and the tyrosine phosphorylation sites within the substrate domain (SD). Expression of wild type p130Cas in Cas -/- mouse embryo fibroblasts resulted in enhanced cell migration associated with increased leading-edge actin flux, increased rates of FA assembly/disassembly, and uninterrupted FA turnover. Variants lacking either the SD phosphorylation sites or the SBD SH3-binding motif were able to partially restore the migration response, while only a variant lacking both signaling functions was fully defective. Notably, the migration defects associated with p130Cas signaling-deficient variants correlated with longer FA lifetimes resulting from aborted FA disassembly attempts. However the SD mutational variant was fully defective in increasing actin assembly at the protruding leading edge and FA assembly/disassembly rates, indicating that SD phosphorylation is the sole p130Cas signaling function in regulating these processes. Our results provide the first quantitative evidence supporting roles for p130Cas SD tyrosine phosphorylation in promoting both leading edge actin flux and FA turnover during cell migration, while further revealing that the p130Cas SBD has a function in cell migration and sustained FA disassembly that is distinct from its known role of promoting SD tyrosine phosphorylation.
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11 MeSH Terms
Dynamics and mechanism of p130Cas localization to focal adhesions.
Donato DM, Ryzhova LM, Meenderink LM, Kaverina I, Hanks SK
(2010) J Biol Chem 285: 20769-79
MeSH Terms: Animals, Antibodies, Monoclonal, Cell Movement, Crk-Associated Substrate Protein, Fibroblasts, Focal Adhesions, Genes, Reporter, Genetic Variation, Immunoblotting, Luminescent Proteins, Mice, Paxillin, Phosphorylation, Plasmids, Polymerase Chain Reaction, Substrate Specificity, Wound Healing, src-Family Kinases
Show Abstract · Added December 10, 2013
The docking protein p130Cas is a major Src substrate involved in integrin signaling and mechanotransduction. Tyrosine phosphorylation of p130Cas in focal adhesions (FAs) has been linked to enhanced cell migration, invasion, proliferation, and survival. However, the mechanism of p130Cas targeting to FAs is uncertain, and dynamic aspects of its localization have not been explored. Using live cell microscopy, we show that fluorophore-tagged p130Cas is a component of FAs throughout the FA assembly and disassembly stages, although it resides transiently in FAs with a high mobile fraction. Deletion of either the N-terminal Src homology 3 (SH3) domain or the Cas-family C-terminal homology (CCH) domain significantly impaired p130Cas FA localization, and deletion of both domains resulted in full exclusion. Focal adhesion kinase was implicated in the FA targeting function of the p130Cas SH3 domain. Consistent with their roles in FA targeting, both the SH3 and CCH domains were found necessary for p130Cas to fully undergo tyrosine phosphorylation and promote cell migration. By revealing the capacity of p130Cas to function in FAs throughout their lifetime, clarifying FA targeting mechanism, and demonstrating the functional importance of the highly conserved CCH domain, our results advance the understanding of an important aspect of integrin signaling.
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18 MeSH Terms
Extracellular matrix rigidity promotes invadopodia activity.
Alexander NR, Branch KM, Parekh A, Clark ES, Iwueke IC, Guelcher SA, Weaver AM
(2008) Curr Biol 18: 1295-1299
MeSH Terms: Actin Cytoskeleton, Azepines, Cell Line, Tumor, Cell Surface Extensions, Crk-Associated Substrate Protein, Enzyme Inhibitors, Extracellular Matrix, Focal Adhesion Kinase 1, Gelatin, Heterocyclic Compounds, 4 or More Rings, Humans, Integrins, Myosin Type II, Myosin-Light-Chain Kinase, Naphthalenes, Signal Transduction
Show Abstract · Added March 5, 2014
Invadopodia are actin-rich subcellular protrusions with associated proteases used by cancer cells to degrade extracellular matrix (ECM) [1]. Molecular components of invadopodia include branched actin-assembly proteins, membrane trafficking proteins, signaling proteins, and transmembrane proteinases [1]. Similar structures exist in nontransformed cells, such as osteoclasts and dendritic cells, but are generally called podosomes and are thought to be more involved in cell-matrix adhesion than invadopodia [2-4]. Despite intimate contact with their ECM substrates, it is unknown whether physical or chemical ECM signals regulate invadopodia function. Here, we report that ECM rigidity directly increases both the number and activity of invadopodia. Transduction of ECM-rigidity signals depends on the cellular contractile apparatus [5-7], given that inhibition of nonmuscle myosin II, myosin light chain kinase, and Rho kinase all abrogate invadopodia-associated ECM degradation. Whereas myosin IIA, IIB, and phosphorylated myosin light chain do not localize to invadopodia puncta, active phosphorylated forms of the mechanosensing proteins p130Cas (Cas) and focal adhesion kinase (FAK) are present in actively degrading invadopodia, and the levels of phospho-Cas and phospho-FAK in invadopodia are sensitive to myosin inhibitors. Overexpression of Cas or FAK further enhances invadopodia activity in cells plated on rigid polyacrylamide substrates. Thus, in invasive cells, ECM-rigidity signals lead to increased matrix-degrading activity at invadopodia, via a myosin II-FAK/Cas pathway. These data suggest a potential mechanism, via invadopodia, for the reported correlation of tissue density with cancer aggressiveness.
2 Communities
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16 MeSH Terms
Targeting SRC family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model.
Park SI, Zhang J, Phillips KA, Araujo JC, Najjar AM, Volgin AY, Gelovani JG, Kim SJ, Wang Z, Gallick GE
(2008) Cancer Res 68: 3323-33
MeSH Terms: Animals, Antineoplastic Agents, Cell Movement, Cell Proliferation, Crk-Associated Substrate Protein, Dasatinib, Disease Models, Animal, Drug Delivery Systems, Focal Adhesion Kinase 1, Humans, Lymphatic Metastasis, Male, Mice, Mice, Nude, Prostatic Neoplasms, Pyrimidines, Thiazoles, Tumor Burden, Tumor Cells, Cultured, Tyrosine, Xenograft Model Antitumor Assays, src-Family Kinases
Show Abstract · Added March 5, 2014
Aberrant expression and/or activity of members of the Src family of nonreceptor protein tyrosine kinases (SFK) are commonly observed in progressive stages of human tumors. In prostate cancer, two SFKs (Src and Lyn) have been specifically implicated in tumor growth and progression. However, there are no data in preclinical models demonstrating potential efficacy of Src inhibitors against prostate cancer growth and/or metastasis. In this study, we used the small molecule SFK/Abl kinase inhibitor dasatinib, currently in clinical trials for solid tumors, to examine in vitro and in vivo effects of inhibiting SFKs in prostate tumor cells. In vitro, dasatinib inhibits both Src and Lyn activity, resulting in decreased cellular proliferation, migration, and invasion. In orthotopic nude mouse models, dasatinib treatment effectively inhibits expression of activated SFKs, resulting in inhibition of both tumor growth and development of lymph node metastases in both androgen-sensitive and androgen-resistant tumors. In primary tumors, SFK inhibition leads to decreased cellular proliferation (determined by immunohistochemistry for proliferating cell nuclear antigen). In vitro, small interfering RNA (siRNA)-mediated inhibition of Lyn affects cellular proliferation; siRNA inhibition of Src affects primarily cellular migration. Therefore, we conclude that SFKs are promising therapeutic targets for treatment of human prostate cancer and that Src and Lyn activities affect different cellular functions required for prostate tumor growth and progression.
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22 MeSH Terms
Distinct roles for p107 and p130 in Rb-independent cellular senescence.
Lehmann BD, Brooks AM, Paine MS, Chappell WH, McCubrey JA, Terrian DM
(2008) Cell Cycle 7: 1262-8
MeSH Terms: Carcinoma, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Cellular Senescence, Crk-Associated Substrate Protein, Cyclin-Dependent Kinase Inhibitor p27, DNA Damage, Down-Regulation, Genes, cdc, Humans, Male, Prostatic Neoplasms, Radiation, Retinoblastoma Protein, Retinoblastoma-Like Protein p107, Tumor Suppressor Proteins
Show Abstract · Added January 20, 2015
Telomere attrition, DNA damage and constitutive mitogenic signaling can all trigger cellular senescence in normal cells and serve as a defense against tumor progression. Cancer cells may circumvent this cellular defense by acquiring genetic mutations in checkpoint proteins responsible for regulating permanent cell cycle arrest. A small family of tumor suppressor genes encoding the retinoblastoma susceptibility protein family (Rb, p107, p130) exerts a partially redundant control of entry into S phase of DNA replication and cellular proliferation. Here we report that activation of the p53-dependent DNA damage response has been found to accelerate senescence in human prostate cancer cells lacking a functional Rb protein. This novel form of irradiation-induced premature cellular senescence reinforces the notion that other Rb family members may compensate for loss of Rb protein in the DNA damage response pathway. Consistent with this hypothesis, depletion of p107 potently inhibits the irradiation-induced senescence observed in DU145 cells. In contrast, p130 depletion triggers a robust and unexpected form of premature senescence in unirradiated cells. The dominant effect of depleting both p107 and p130, in the absence of Rb, was a complete blockade of irradiation-induced cellular senescence. Onset of the p107-dependent senescence was temporally associated with p53-mediated stabilization of the cyclin-dependent kinase inhibitor p27 and decreases in c-myc and cks1 expression. These results indicate that p107 is required for initiation of accelerated cellular senescence in the absence of Rb and introduces the concept that p130 may be required to prevent the onset of terminal growth arrest in unstimulated prostate cancer cells lacking a functional Rb allele.
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17 MeSH Terms
The integrin-coupled signaling adaptor p130Cas suppresses Smad3 function in transforming growth factor-beta signaling.
Kim W, Seok Kang Y, Soo Kim J, Shin NY, Hanks SK, Song WK
(2008) Mol Biol Cell 19: 2135-46
MeSH Terms: Animals, Cell Cycle, Cell Nucleus, Cell Proliferation, Cells, Cultured, Crk-Associated Substrate Protein, Extracellular Matrix, Humans, Integrins, Mice, Phosphorylation, Phosphotyrosine, Protein Binding, Protein Transport, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad3 Protein, Transcription, Genetic, Transforming Growth Factor beta
Show Abstract · Added January 20, 2015
Reciprocal cooperative signaling by integrins and growth factor receptors at G1 phase during cell cycle progression is well documented. By contrast, little is known about the cross-talk between integrin and transforming growth factor (TGF)-beta signaling. Here, we show that integrin signaling counteracts the inhibitory effects of TGF-beta on cell growth and that this effect is mediated by p130Cas (Crk-associated substrate, 130 kDa). Adhesion to fibronectin or laminin reduces TGF-beta-induced Smad3 phosphorylation and thus inhibits TGF-beta-mediated growth arrest; loss of p130Cas abrogates these effects. Loss and gain of function studies demonstrated that, once tyrosine-phosphorylated via integrin signaling, p130Cas binds to Smad3 and reduces phosphorylation of Smad3. That in turn leads to inhibition of p15 and p21 expression and facilitation of cell cycle progression. Thus, p130Cas-mediated control of TGF-beta/Smad signaling may provide an additional clue to the mechanism underlying resistance to TGF-beta-induced growth inhibition.
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19 MeSH Terms
p130CAS is required for netrin signaling and commissural axon guidance.
Liu G, Li W, Gao X, Li X, Jürgensen C, Park HT, Shin NY, Yu J, He ML, Hanks SK, Wu JY, Guan KL, Rao Y
(2007) J Neurosci 27: 957-68
MeSH Terms: Animals, Axons, Cell Line, Cells, Cultured, Chick Embryo, Crk-Associated Substrate Protein, Female, Humans, MAP Kinase Signaling System, Mice, Nerve Growth Factors, Netrin-1, Pregnancy, Tumor Suppressor Proteins, rac1 GTP-Binding Protein
Show Abstract · Added January 20, 2015
Netrins are an important family of axon guidance cues. Here, we report that netrin-1 induces tyrosine phosphorylation of p130(CAS) (Crk-associated substrate). Our biochemical studies indicate that p130(CAS) is downstream of the Src family kinases and upstream of the small GTPase Rac1 and Cdc42. Inhibition of p130(CAS) signaling blocks both the neurite outgrowth-promoting activity and the axon attraction activity of netrin-1. p130(CAS) RNA interference inhibits the attraction of commissural axons in the spinal cord by netrin-1 and causes defects in commissural axon projection in the embryo. These results demonstrate that p130(CAS) is a key component in the netrin signal transduction pathway and plays an important role in guiding commissural axons in vivo.
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15 MeSH Terms