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The SRC-associated protein CUB Domain-Containing Protein-1 regulates adhesion and motility

Oncogene volume 31, pages 653–663 (2012)Cite this article

Abstract

Multiple SRC-family kinases (SFKs) are commonly activated in carcinoma and appear to have a role in metastasis through incompletely understood mechanisms. Recent studies have shown that CDCP1 (CUB (complement C1r/C1s, Uegf, Bmp1) Domain-Containing Protein-1) is a transmembrane protein and an SRC substrate potentially involved in metastasis. Here we show that increased SFK and CDCP1 tyrosine phosphorylation is, surprisingly, associated with a decrease in FAK phosphorylation. This appears to be true in human tumors as shown by our correlation analysis of a mass spectrometric data set of affinity-purified phosphotyrosine peptides obtained from normal and cancer lung tissue samples. Induction of tyrosine phosphorylation of CDCP1 in cell culture, including by a mAb that binds to its extracellular domain, promoted changes in SFK and FAK tyrosine phosphorylation, as well as in PKCTM, a protein known to associate with CDCP1, and these changes are accompanied by increases in adhesion and motility. Thus, signaling events that accompany the CDCP1 tyrosine phosphorylation observed in cell lines and human lung tumors may explain how the CDCP1/SFK complex regulates motility and adhesion.

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References

  • Aligayer H, Boyd DD, Heiss MM, Abdalla EK, Curley SA, Gallick GE . (2002). Activation of Src kinase in primary colorectal carcinoma: an indicator of poor clinical prognosis. Cancer 94: 344–351.

    Article  PubMed  Google Scholar 

  • Alvares SM, Dunn CA, Brown TA, Wayner EE, Carter WG . (2008). The role of membrane microdomains in transmembrane signaling through the epithelial glycoprotein Gp140/CDCP1. Biochim Biophys Acta 1780: 486–496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Awakura Y, Nakamura E, Takahashi T, Kotani H, Mikami Y, Kadowaki T et al. (2008). Microarray-based identification of CUB-domain containing protein 1 as a potential prognostic marker in conventional renal cell carcinoma. J Cancer Res Clin Oncol 134: 1363–1369.

    Article  CAS  PubMed  Google Scholar 

  • Benes CH, Wu N, Elia AE, Dharia T, Cantley LC, Soltoff SP . (2005). The C2 domain of PKCdelta is a phosphotyrosine binding domain. Cell 121: 271–280.

    Article  CAS  PubMed  Google Scholar 

  • Bhatt AS, Erdjument-Bromage H, Tempst P, Craik CS, Moasser MM . (2005). Adhesion signaling by a novel mitotic substrate of src kinases. Oncogene 24: 5333–5343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bolen JB, Veillette A, Schwartz AM, DeSeau V, Rosen N . (1987). Activation of pp60c-src protein kinase activity in human colon carcinoma. Proc Natl Acad Sci USA 84: 2251–2255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bromann PA, Korkaya H, Courtneidge SA . (2004). The interplay between Src family kinases and receptor tyrosine kinases. Oncogene 23: 7957–7968.

    Article  CAS  PubMed  Google Scholar 

  • Brunton VG, Avizienyte E, Fincham VJ, Serrels B, Metcalf III CA, Sawyer TK et al. (2005). Identification of Src-specific phosphorylation site on focal adhesion kinase: dissection of the role of Src SH2 and catalytic functions and their consequences for tumor cell behavior. Cancer Res 65: 1335–1342.

    Article  CAS  PubMed  Google Scholar 

  • Brunton VG, Frame MC . (2008). Src and focal adhesion kinase as therapeutic targets in cancer. Curr Opin Pharmacol 8: 427–432.

    Article  CAS  PubMed  Google Scholar 

  • Buhring HJ, Kuci S, Conze T, Rathke G, Bartolovic K, Grunebach F et al. (2004). CDCP1 identifies a broad spectrum of normal and malignant stem/progenitor cell subsets of hematopoietic and nonhematopoietic origin. Stem Cells 22: 334–343.

    Article  PubMed  Google Scholar 

  • Cartwright CA, Kamps MP, Meisler AI, Pipas JM, Eckhart W . (1989). pp60c-src activation in human colon carcinoma. J Clin Invest 83: 2025–2033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan KT, Cortesio CL, Huttenlocher A . (2009). FAK alters invadopodia and focal adhesion composition and dynamics to regulate breast cancer invasion. J Cell Biol 185: 357–370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cooper JA, Qian H . (2008). A mechanism for SRC kinase-dependent signaling by noncatalytic receptors. Biochemistry 47: 5681–5688.

    Article  CAS  PubMed  Google Scholar 

  • Courtneidge SA . (2002). Role of Src in signal transduction pathways. The Jubilee Lecture. Biochem Soc Trans 30: 11–17.

    Article  CAS  PubMed  Google Scholar 

  • Deryugina EI, Conn EM, Wortmann A, Partridge JJ, Kupriyanova TA, Ardi VC et al. (2009). Functional role of cell surface CUB domain-containing protein 1 in tumor cell dissemination. Mol Cancer Res 7: 1197–1211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frame MC . (2002). Src in cancer: deregulation and consequences for cell behaviour. Biochim Biophys Acta 1602: 114–130.

    CAS  PubMed  Google Scholar 

  • Frame MC . (2004). Newest findings on the oldest oncogene; how activated src does it. J Cell Sci 117: 989–998.

    Article  CAS  PubMed  Google Scholar 

  • He Y, Wortmann A, Burke LJ, Reid JC, Adams MN, Abdul-Jabbar I et al. (2010). Proteolysis-induced N-terminal ectodomain shedding of the integral membrane glycoprotein CUB domain-containing protein 1 (CDCP1) is accompanied by tyrosine phosphorylation of its C-terminal domain and recruitment of Src and PKCdelta. J Biol Chem 285: 26162–26173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hooper JD, Zijlstra A, Aimes RT, Liang H, Claassen GF, Tarin D et al. (2003). Subtractive immunization using highly metastatic human tumor cells identifies SIMA135/CDCP1, a 135 kDa cell surface phosphorylated glycoprotein antigen. Oncogene 22: 1783–1794.

    Article  CAS  PubMed  Google Scholar 

  • Huveneers S, Danen EH . (2009). Adhesion signaling—crosstalk between integrins, Src and Rho. J Cell Sci 122: 1059–1069.

    Article  CAS  PubMed  Google Scholar 

  • Ikeda J, Oda T, Inoue M, Uekita T, Sakai R, Okumura M et al. (2009). Expression of CUB domain containing protein (CDCP1) is correlated with prognosis and survival of patients with adenocarcinoma of lung. Cancer Sci 100: 429–433.

    Article  CAS  PubMed  Google Scholar 

  • Ilic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N et al. (1995). Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377: 539–544.

    Article  CAS  PubMed  Google Scholar 

  • Klinghoffer RA, Sachsenmaier C, Cooper JA, Soriano P . (1999). Src family kinases are required for integrin but not PDGFR signal transduction. EMBO J 18: 2459–2471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leroy C, Fialin C, Sirvent A, Simon V, Urbach S, Poncet J et al. (2009). Quantitative phosphoproteomics reveals a cluster of tyrosine kinases that mediates SRC invasive activity in advanced colon carcinoma cells. Cancer Res 69: 2279–2286.

    Article  CAS  PubMed  Google Scholar 

  • Liu H, Ong SE, Badu-Nkansah K, Schindler J, White FM, Hynes RO . (2011). CUB-domain-containing protein 1 (CDCP1) activates Src to promote melanoma metastasis. Proc Natl Acad Sci USA 108: 1379–1384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu Z, Jiang G, Blume-Jensen P, Hunter T . (2001). Epidermal growth factor-induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase. Mol Cell Biol 21: 4016–4031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manes S, Mira E, Gomez-Mouton C, Zhao ZJ, Lacalle RA, Martinez AC . (1999). Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility. Mol Cell Biol 19: 3125–3135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGlade J, Cheng A, Pelicci G, Pelicci PG, Pawson T . (1992). Shc proteins are phosphorylated and regulated by the v-Src and v-Fps protein-tyrosine kinases. Proc Natl Acad Sci USA 89: 8869–8873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McLean GW, Carragher NO, Avizienyte E, Evans J, Brunton VG, Frame MC . (2005). The role of focal-adhesion kinase in cancer—a new therapeutic opportunity. Nat Rev Cancer 5: 505–515.

    Article  CAS  PubMed  Google Scholar 

  • Mitra SK, Hanson DA, Schlaepfer DD . (2005). Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 6: 56–68.

    Article  CAS  PubMed  Google Scholar 

  • Mitra SK, Schlaepfer DD . (2006). Integrin-regulated FAK–Src signaling in normal and cancer cells. Curr Opin Cell Biol 18: 516–523.

    Article  CAS  PubMed  Google Scholar 

  • Miyazawa Y, Uekita T, Hiraoka N, Fujii S, Kosuge T, Kanai Y et al. (2010). CUB domain-containing protein 1, a prognostic factor for human pancreatic cancers, promotes cell migration and extracellular matrix degradation. Cancer Res 70: 5136–5146.

    Article  CAS  PubMed  Google Scholar 

  • Perry SE, Robinson P, Melcher A, Quirke P, Buhring HJ, Cook GP et al. (2007). Expression of the CUB domain containing protein 1 (CDCP1) gene in colorectal tumour cells. FEBS Lett 581: 1137–1142.

    Article  CAS  PubMed  Google Scholar 

  • Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H et al. (2007). Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131: 1190–1203.

    Article  CAS  PubMed  Google Scholar 

  • Scherl-Mostageer M, Sommergruber W, Abseher R, Hauptmann R, Ambros P, Schweifer N . (2001). Identification of a novel gene, CDCP1, overexpressed in human colorectal cancer. Oncogene 20: 4402–4408.

    Article  CAS  PubMed  Google Scholar 

  • Serrels A, Macpherson IR, Evans TR, Lee FY, Clark EA, Sansom OJ et al. (2006). Identification of potential biomarkers for measuring inhibition of Src kinase activity in colon cancer cells following treatment with dasatinib. Mol Cancer Ther 5: 3014–3022.

    Article  CAS  PubMed  Google Scholar 

  • Serrels B, Serrels A, Brunton VG, Holt M, McLean GW, Gray CH et al. (2007). Focal adhesion kinase controls actin assembly via a FERM-mediated interaction with the Arp2/3 complex. Nat Cell Biol 9: 1046–1056.

    Article  CAS  PubMed  Google Scholar 

  • Sieg DJ, Hauck CR, Ilic D, Klingbeil CK, Schaefer E, Damsky CH et al. (2000). FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol 2: 249–256.

    Article  CAS  PubMed  Google Scholar 

  • Sieg DJ, Hauck CR, Schlaepfer DD . (1999). Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. J Cell Sci 112 (Pt 16): 2677–2691.

    CAS  PubMed  Google Scholar 

  • Smyth GK . (2004). Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3: Article3.

    Article  PubMed  Google Scholar 

  • Spassov DS, Baehner FL, Wong CH, McDonough S, Moasser MM . (2009). The transmembrane src substrate Trask is an epithelial protein that signals during anchorage deprivation. Am J Pathol 174: 1756–1765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spassov DS, Wong CH, Sergina N, Ahuja D, Fried M, Sheppard D et al. (2011). Phosphorylation of Trask by Src kinases inhibits integrin clustering and functions in exclusion with focal adhesion signaling. Mol Cell Biol 31: 766–782.

    Article  CAS  PubMed  Google Scholar 

  • Talamonti MS, Roh MS, Curley SA, Gallick GE . (1993). Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer. J Clin Invest 91: 53–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tilghman RW, Slack-Davis JK, Sergina N, Martin KH, Iwanicki M, Hershey ED et al. (2005). Focal adhesion kinase is required for the spatial organization of the leading edge in migrating cells. J Cell Sci 118: 2613–2623.

    Article  CAS  PubMed  Google Scholar 

  • Uekita T, Jia L, Narisawa-Saito M, Yokota J, Kiyono T, Sakai R . (2007). CUB domain-containing protein 1 is a novel regulator of anoikis resistance in lung adenocarcinoma. Mol Cell Biol 27: 7649–7660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uekita T, Tanaka M, Takigahira M, Miyazawa Y, Nakanishi Y, Kanai Y et al. (2008). CUB-domain-containing protein 1 regulates peritoneal dissemination of gastric scirrhous carcinoma. Am J Pathol 172: 1729–1739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vitale S, Avizienyte E, Brunton VG, Frame MC . (2008). Focal adhesion kinase is not required for Src-induced formation of invadopodia in KM12C colon cancer cells and can interfere with their assembly. Eur J Cell Biol 87: 569–579.

    Article  CAS  PubMed  Google Scholar 

  • Vultur A, Buettner R, Kowolik C, Liang W, Smith D, Boschelli F et al. (2008). SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells. Mol Cancer Ther 7: 1185–1194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wortmann A, He Y, Deryugina EI, Quigley JP, Hooper JD . (2009). The cell surface glycoprotein CDCP1 in cancer—insights, opportunities, and challenges. IUBMB Life 61: 723–730.

    Article  CAS  PubMed  Google Scholar 

  • Yu DH, Qu CK, Henegariu O, Lu X, Feng GS . (1998). Protein-tyrosine phosphatase Shp-2 regulates cell spreading, migration, and focal adhesion. J Biol Chem 273: 21125–21131.

    Article  CAS  PubMed  Google Scholar 

  • Zhang SQ, Yang W, Kontaridis MI, Bivona TG, Wen G, Araki T et al. (2004). Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment. Mol Cell 13: 341–355.

    Article  PubMed  Google Scholar 

  • Zheng Y, Xia Y, Hawke D, Halle M, Tremblay ML, Gao X et al. (2009). FAK phosphorylation by ERK primes ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST. Mol Cell 35: 11–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. C H Benes

    Present address: 3Current address: Massachusetts General Hospital Cancer Center, 149, 13th Street, Charlestown, MA 02129, USA.,

Authors and Affiliations

  1. Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA, USA

    C H Benes, G Poulogiannis, L C Cantley & S P Soltoff

  2. Department of Systems Biology, Harvard Medical School, Boston, MA, USA

    G Poulogiannis & L C Cantley

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Correspondence to S P Soltoff.

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Benes, C., Poulogiannis, G., Cantley, L. et al. The SRC-associated protein CUB Domain-Containing Protein-1 regulates adhesion and motility. Oncogene 31, 653–663 (2012). https://doi.org/10.1038/onc.2011.262

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