crk associated substrate protein


Summary: Crk-associated substrate was originally identified as a highly phosphorylated 130 kDa protein that associates with ONCOGENE PROTEIN CRK and ONCOGENE PROTEIN SRC. It is a signal transducing adaptor protein that undergoes tyrosine PHOSPHORYLATION in signaling pathways that regulate CELL MIGRATION and CELL PROLIFERATION.

Top Publications

  1. Patwardhan P, Shen Y, Goldberg G, Miller W. Individual Cas phosphorylation sites are dispensable for processive phosphorylation by Src and anchorage-independent cell growth. J Biol Chem. 2006;281:20689-97 pubmed
    ..Mutants lacking some or all YXXP sites augment the ability of Src to promote anchorage-independent growth. On the other hand, deletion of YXXP sites compromises the ability of Cas to promote tumor cell migration. ..
  2. Nikolic I, Kastratovic T, Zelen I, Zivanovic A, Arsenijevic S, Mitrovic M. Cytosolic pro-apoptotic SPIKE induces mitochondrial apoptosis in cancer. Biochem Biophys Res Commun. 2010;395:225-31 pubmed publisher
    ..Although the informatics analysis of SPIKE implicates this protein as a member of the BH3-only BCL-2 subfamily, its role in apoptosis remains to be elucidated. ..
  3. Yadav S, Yeh B, Craddock B, Lim W, Miller W. Reengineering the signaling properties of a Src family kinase. Biochemistry. 2009;48:10956-62 pubmed publisher
    ..Thus, the PDZ-ligand interaction is able to functionally replace the normal SH2-pY527 interaction that regulates SFKs. Our data highlight the modularity and evolvability of signaling proteins. ..
  4. Patwardhan P, Miller W. Processive phosphorylation: mechanism and biological importance. Cell Signal. 2007;19:2218-26 pubmed
    ..Finally, we contrast the biological situations that are suited to regulation by processive and non-processive phosphorylation. ..
  5. Tazaki T, Sasaki T, Uto K, Yamasaki N, Tashiro S, Sakai R, et al. p130Cas, Crk-associated substrate plays essential roles in liver development by regulating sinusoidal endothelial cell fenestration. Hepatology. 2010;52:1089-99 pubmed publisher
    ..Cas plays pivotal roles in liver development through the reorganization of the actin cytoskeleton and formation of fenestrae in SECs. ..
  6. Gupta S, Vlahakis N. Integrin alpha9beta1 mediates enhanced cell migration through nitric oxide synthase activity regulated by Src tyrosine kinase. J Cell Sci. 2009;122:2043-54 pubmed publisher
    ..When taken together, our results describe a novel and unique mechanism of coordinated interactions of the integrin alpha9 cytoplasmic domain, Src tyrosine kinase and iNOS to transduce integrin-alpha9beta1-mediated cell migration. ..
  7. Gonzalo P, Guadamillas M, Hernández Riquer M, Pollán A, Grande García A, Bartolomé R, et al. MT1-MMP is required for myeloid cell fusion via regulation of Rac1 signaling. Dev Cell. 2010;18:77-89 pubmed publisher
  8. Shiratsuchi H, Kouatli Y, Yu G, Marsh H, Basson M. Propofol inhibits pressure-stimulated macrophage phagocytosis via the GABAA receptor and dysregulation of p130cas phosphorylation. Am J Physiol Cell Physiol. 2009;296:C1400-10 pubmed publisher
    ..p130cas may be an important target for modulation of macrophage function in anesthetized patients. ..
  9. Wendt M, Smith J, Schiemann W. p130Cas is required for mammary tumor growth and transforming growth factor-beta-mediated metastasis through regulation of Smad2/3 activity. J Biol Chem. 2009;284:34145-56 pubmed publisher

More Information


  1. Zhang W, Li J, Kanginakudru S, Zhao W, Yu X, Chen J. The human papillomavirus type 58 E7 oncoprotein modulates cell cycle regulatory proteins and abrogates cell cycle checkpoints. Virology. 2010;397:139-44 pubmed publisher
  2. Wohlschlaeger J, Schmitz K, Takeda A, Takeda N, Vahlhaus C, Stypmann J, et al. Reversible regulation of the retinoblastoma protein/E2F-1 pathway during "reverse cardiac remodelling" after ventricular unloading. J Heart Lung Transplant. 2010;29:117-24 pubmed publisher
    ..These data underscore the importance of cell cycle regulatory proteins in the pathogenesis of CHF-associated (maladaptive) cardiomyocyte hypertrophy and might offer novel clues for pharmacologic approaches of congestive heart failure. ..
  3. Jia L, Tang D. Abl activation regulates the dissociation of CAS from cytoskeletal vimentin by modulating CAS phosphorylation in smooth muscle. Am J Physiol Cell Physiol. 2010;299:C630-7 pubmed publisher
    ..These results suggest that Abl regulates the dissociation of CAS from the vimentin network, actin polymerization, and contraction by modulating CAS phosphorylation in smooth muscle. ..
  4. Robinson L, Yaroslavskiy B, Griswold R, Zadorozny E, Guo L, Tourkova I, et al. Estrogen inhibits RANKL-stimulated osteoclastic differentiation of human monocytes through estrogen and RANKL-regulated interaction of estrogen receptor-alpha with BCAR1 and Traf6. Exp Cell Res. 2009;315:1287-301 pubmed publisher
    ..We conclude that estrogen directly, but only partially, curtails human osteoclast formation. This effect requires BCAR1 and involves a non-genomic interaction with ERalpha. ..
  5. Mannefeld M, Klassen E, Gaubatz S. B-MYB is required for recovery from the DNA damage-induced G2 checkpoint in p53 mutant cells. Cancer Res. 2009;69:4073-80 pubmed publisher
    ..Taken together, these data suggest that B-MYB/LINC plays an important role in the DNA damage response downstream of p53. ..
  6. Makkinje A, Near R, Infusini G, Vanden Borre P, Bloom A, Cai D, et al. AND-34/BCAR3 regulates adhesion-dependent p130Cas serine phosphorylation and breast cancer cell growth pattern. Cell Signal. 2009;21:1423-35 pubmed publisher
  7. Cabodi S, Tinnirello A, Bisaro B, Tornillo G, del Pilar Camacho Leal M, Forni G, et al. p130Cas is an essential transducer element in ErbB2 transformation. FASEB J. 2010;24:3796-808 pubmed publisher
    ..These results demonstrate that p130Cas is an essential transducer in ErbB2 transformation and highlight its potential use as a novel therapeutic target in ErbB2 positive human breast cancers...
  8. Schuh N, Guerrero M, Schrecengost R, Bouton A. BCAR3 regulates Src/p130 Cas association, Src kinase activity, and breast cancer adhesion signaling. J Biol Chem. 2010;285:2309-17 pubmed publisher
    ..Based on these data, we propose that the c-Src/Cas/BCAR3 signaling axis is a prominent regulator of c-Src activity, which in turn controls cell behaviors that lead to aggressive and invasive breast tumor phenotypes. ..
  9. Singh M, Nicolas E, Gherraby W, Dadke D, Lessin S, Golemis E. HEI10 negatively regulates cell invasion by inhibiting cyclin B/Cdk1 and other promotility proteins. Oncogene. 2007;26:4825-32 pubmed
    ..Finally, HEI10 is abundantly transcribed in many human tissues, and particularly abundant in some tumor cell lines, suggesting that it may be commonly involved in coordinating cell cycle with cell migration and invasion. ..
  10. Wang R, Li Q, Anfinogenova Y, Tang D. Dissociation of Crk-associated substrate from the vimentin network is regulated by p21-activated kinase on ACh activation of airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2007;292:L240-8 pubmed
    ..The PAK-mediated dissociation of CAS from the vimentin network may participate in the cellular processes that affect active force development during ACh activation of tracheal smooth muscle tissues. ..
  11. Godinho M, Sieuwerts A, Look M, Meijer D, Foekens J, Dorssers L, et al. Relevance of BCAR4 in tamoxifen resistance and tumour aggressiveness of human breast cancer. Br J Cancer. 2010;103:1284-91 pubmed publisher
    ..Our cell model suggests that BCAR4-positive breast tumours are driven by ERBB2/ERBB3 signalling. Patients with such tumours may benefit from ERBB-targeted therapy. ..
  12. Fraley S, Feng Y, Krishnamurthy R, Kim D, Celedon A, Longmore G, et al. A distinctive role for focal adhesion proteins in three-dimensional cell motility. Nat Cell Biol. 2010;12:598-604 pubmed publisher
    ..This study shows that membrane protrusions constitute a critical motility/matrix-traction module that drives cell motility in a 3D matrix. ..
  13. Hegan D, Lu Y, Stachelek G, Crosby M, Bindra R, Glazer P. Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci U S A. 2010;107:2201-6 pubmed publisher
    ..This work identifies a mechanism by which PARP regulates DNA repair and suggests new strategies for combination cancer therapies. ..
  14. Ohkawa Y, Miyazaki S, Hamamura K, Kambe M, Miyata M, Tajima O, et al. Ganglioside GD3 enhances adhesion signals and augments malignant properties of melanoma cells by recruiting integrins to glycolipid-enriched microdomains. J Biol Chem. 2010;285:27213-23 pubmed publisher
    ..All these results suggested that integrins assembled and formed a cluster in GEM/rafts, leading to the enhanced signaling and malignant properties under GD3 expression. ..
  15. Anfinogenova Y, Wang R, Li Q, Spinelli A, Tang D. Abl silencing inhibits CAS-mediated process and constriction in resistance arteries. Circ Res. 2007;101:420-8 pubmed
    ..Abl does not participate in the regulation of myosin activation in arterial vessels during contractile stimulation. ..
  16. Soni S, Lin B, August A, Nicholson R, Kirsch K. Expression of a phosphorylated p130(Cas) substrate domain attenuates the phosphatidylinositol 3-kinase/Akt survival pathway in tamoxifen resistant breast cancer cells. J Cell Biochem. 2009;107:364-75 pubmed publisher
    ..Therefore, our findings suggest that targeting the product of the BCAR1 gene by a peptide which mimics the phosphorylated substrate domain may provide a new molecular avenue for treatment of antiestrogen resistant breast cancers. ..
  17. Alexandropoulos K, Regelmann A. Regulation of T-lymphocyte physiology by the Chat-H/CasL adapter complex. Immunol Rev. 2009;232:160-74 pubmed publisher
    ..Here we review our current knowledge of how Chat-H and Hef1/CasL regulate T-cell physiology and whether this protein complex plays a functional role downstream of T-cell receptor activation. ..
  18. Agle K, Vongsa R, Dwinell M. Calcium mobilization triggered by the chemokine CXCL12 regulates migration in wounded intestinal epithelial monolayers. J Biol Chem. 2010;285:16066-75 pubmed publisher
    ..These results suggest CXCL12 regulates restitution through calcium-activated Pyk2 localized to active focal adhesions. Calcium signaling pathways may therefore provide a novel avenue for enhancing barrier repair. ..
  19. Halle M, Gomez M, Stuible M, Shimizu H, McMaster W, Olivier M, et al. The Leishmania surface protease GP63 cleaves multiple intracellular proteins and actively participates in p38 mitogen-activated protein kinase inactivation. J Biol Chem. 2009;284:6893-908 pubmed publisher
    ..Our results establish that GP63 plays a central role in a number of hostcell molecular events that likely contribute to the infectivity of Leishmania. ..
  20. Tang D. p130 Crk-associated substrate (CAS) in vascular smooth muscle. J Cardiovasc Pharmacol Ther. 2009;14:89-98 pubmed publisher
    ..The CAS-associated processes may be new biological targets for the development of new treatment of cardiovascular diseases such as hypertension. ..
  21. Basuroy S, DUNAGAN M, Sheth P, Seth A, Rao R. Hydrogen peroxide activates focal adhesion kinase and c-Src by a phosphatidylinositol 3 kinase-dependent mechanism and promotes cell migration in Caco-2 cell monolayers. Am J Physiol Gastrointest Liver Physiol. 2010;299:G186-95 pubmed publisher
    ..This study shows that oxidative stress activates FAK and accelerates cell migration in an intestinal epithelium by a PI3 kinase- and Src kinase-dependent mechanism. ..
  22. Liu Z, Adams H, Whitehead I. The rho-specific guanine nucleotide exchange factor Dbs regulates breast cancer cell migration. J Biol Chem. 2009;284:15771-80 pubmed publisher
    ..This suggests that Dbs activates Cdc42 in these two human breast cancer cell lines and that the normal function of Dbs may be required to support cell movement. ..
  23. Curcio M, Batista W, Linares E, Nascimento F, Moraes M, Borges R, et al. Regulatory effects of nitric oxide on Src kinase, FAK, p130Cas, and receptor protein tyrosine phosphatase alpha (PTP-alpha): a role for the cellular redox environment. Antioxid Redox Signal. 2010;13:109-25 pubmed publisher
    ..SNAP differentially stimulated cell proliferation of both cell lines is dependent on the intracellular redox environment, Src activity, and PTP-alpha expression. This dependence also is observed with FBS-stimulated cell migration. ..
  24. van Agthoven T, Sieuwerts A, Meijer D, Meijer van Gelder M, van Agthoven T, Sarwari R, et al. Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response. Endocr Relat Cancer. 2010;17:215-30 pubmed publisher
  25. Kim L, Song L, Haura E. Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol. 2009;6:587-95 pubmed publisher
    ..In preclinical studies these agents can suppress tumor growth and metastases. The agents seem to be safe in humans and could add to the therapeutic arsenal against subsets of cancers. ..
  26. Brinkman A, de Jong D, Tuinman S, Azaouagh N, van Agthoven T, Dorssers L. The substrate domain of BCAR1 is essential for anti-estrogen-resistant proliferation of human breast cancer cells. Breast Cancer Res Treat. 2010;120:401-8 pubmed publisher
    ..This information may also help to devise alternative personalized treatment strategies with improved outcome for breast cancer patients. ..
  27. Shen Y, Chen C, Ichikawa H, Goldberg G. SRC induces podoplanin expression to promote cell migration. J Biol Chem. 2010;285:9649-56 pubmed publisher
    ..These genes encode growth factor receptors, adaptor proteins, and products that have not yet been annotated and may play important roles in tumor cell growth and migration...
  28. Chen S, Wang R, Li Q, Tang D. Abl knockout differentially affects p130 Crk-associated substrate, vinculin, and paxillin in blood vessels of mice. Am J Physiol Heart Circ Physiol. 2009;297:H533-9 pubmed publisher
    ..The Abl-regulated cellular process and blood pressure are independent of myosin activation in vascular smooth muscle. ..
  29. Bigarella C, Borges L, Costa F, Saad S. ARHGAP21 modulates FAK activity and impairs glioblastoma cell migration. Biochim Biophys Acta. 2009;1793:806-16 pubmed publisher
    ..These results suggest not only that ARHGAP21 might act as a tumor suppressor gene, but also indicate that ARHGAP21 might be a master regulator of migration having a crucial role in controlling the progression of different tumor types. ..
  30. Roselli S, Wallez Y, Wang L, Vervoort V, Pasquale E. The SH2 domain protein Shep1 regulates the in vivo signaling function of the scaffolding protein Cas. Cell Signal. 2010;22:1745-52 pubmed publisher
    ..These data demonstrate that Shep1 plays a critical role in the in vivo regulation of Src activity and Cas downstream signaling through Crk, and suggest that the SH2 domain of Shep1 is critical for these effects. ..
  31. Near R, Smith R, Toselli P, Freddo T, Bloom A, Vanden Borre P, et al. Loss of AND-34/BCAR3 expression in mice results in rupture of the adult lens. Mol Vis. 2009;15:685-99 pubmed
  32. Donato D, Ryzhova L, Meenderink L, Kaverina I, Hanks S. Dynamics and mechanism of p130Cas localization to focal adhesions. J Biol Chem. 2010;285:20769-79 pubmed publisher
  33. Patwardhan P, Shiba K, Gordon C, Craddock B, Tamiko M, Miller W. Synthesis of functional signaling domains by combinatorial polymerization of phosphorylation motifs. ACS Chem Biol. 2009;4:751-8 pubmed publisher
    ..Our results suggest that the arrangement of Cas motifs is not critical for signaling. This method could be used to identify the minimal functional units in other signaling proteins. ..
  34. Funasaka K, Ito S, Hasegawa H, Goldberg G, Hirooka Y, Goto H, et al. Cas utilizes Nck2 to activate Cdc42 and regulate cell polarization during cell migration in response to wound healing. FEBS J. 2010;277:3502-13 pubmed publisher
    ..These results indicate that Cas utilizes Nck2 and CrkII in a coordinated set of distinct pathways leading to cell migration. ..
  35. Tikhmyanova N, Little J, Golemis E. CAS proteins in normal and pathological cell growth control. Cell Mol Life Sci. 2010;67:1025-48 pubmed publisher
    ..This review will explore the roles of the CAS proteins in normal and pathological states in the context of the many mechanistic insights into CAS protein function that have emerged in the past decade. ..
  36. Barrow Laing L, Chen W, Roman A. Low- and high-risk human papillomavirus E7 proteins regulate p130 differently. Virology. 2010;400:233-9 pubmed publisher
    ..Inhibition of proteasomal degradation extended the half-life of p130, regardless of intracellular localization. These results suggest that there may be divergent mechanisms by which LR and HR HPV E7 target p130 for degradation. ..
  37. Fan Z, Tardif G, Hum D, Duval N, Pelletier J, Martel Pelletier J. Hsp90{beta} and p130(cas): novel regulatory factors of MMP-13 expression in human osteoarthritic chondrocytes. Ann Rheum Dis. 2009;68:976-82 pubmed publisher
    ..This study illustrates the complex regulation of MMP-13 by showing the inhibitory effect of the two cytoplasmic molecules, p130(cas) and Hsp90beta, in L-OA chondrocytes. ..