Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

A tumor-suppressing function in the epithelial adhesion protein Trask

Oncogene volume 31, pages 419–431 (2012)Cite this article

Abstract

Trask/CDCP1 is a transmembrane glycoprotein widely expressed in epithelial tissues whose functions are just beginning to be understood, but include a role as an anti-adhesive effector of Src kinases. Early studies looking at RNA transcript levels seemed to suggest overexpression in some cancers, but immunostaining studies are now providing more accurate analyses of its expression. In an immuno-histochemical survey of human cancer specimens, we find that Trask expression is retained, reduced or sometimes lost in some tumors compared with their normal epithelial tissue counterparts. A survey of human cancer cell lines also show a similar wide variation in the expression of Trask, including some cell types with the loss of Trask expression, and additional cell types that have lost the physiological detachment-induced phosphorylation of Trask. Three experimental models were established to interrogate the role of Trask in tumor progression, including two gain-of-function models with tet-inducible expression of Trask in tumor cells lacking Trask expression, and one loss-of-function model to suppress Trask expression in tumor cells with abundant Trask expression. The induction of Trask expression and phosphorylation in MCF-7 cells and in 3T3v-src cells was associated with a reduction in tumor metastases while the shRNA-induced knockdown of Trask in L3.6pl cancer cells was associated with increased tumor metastases. The results from these three models are consistent with a tumor-suppressing role for Trask. These data identify Trask as one of several potential candidates for functionally relevant tumor suppressors on the 3p21.3 region of the genome frequently lost in human cancers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Abdel-Ghany M, Cheng HC, Elble RC, Pauli BU . (2002). Focal adhesion kinase activated by beta(4) integrin ligation to mCLCA1 mediates early metastatic growth. J Biol Chem 277: 34391–34400.

    Article  CAS  PubMed  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 

  • 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 

  • Brakebusch C, Bouvard D, Stanchi F, Sakai T, Fassler R . (2002). Integrins in invasive growth. J Clin Invest 109: 999–1006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown TA, Yang TM, Zaitsevskaia T, Xia Y, Dunn CA, Sigle RO et al. (2004). Adhesion or plasmin regulates tyrosine phosphorylation of a novel membrane glycoprotein p80/gp140/CUB domain-containing protein 1 in epithelia. J Biol Chem 279: 14772–14783.

    Article  CAS  PubMed  Google Scholar 

  • Chen JS, Huang XH, Wang Q, Chen XL, Fu XH, Tan HX et al. (2010). FAK is involved in invasion and metastasis of hepatocellular carcinoma. Clin Exp Metastasis 27: 71–82.

    Article  PubMed  Google Scholar 

  • Conze T, Lammers R, Kuci S, Scherl-Mostageer M, Schweifer N, Kanz L et al. (2003). CDCP1 is a novel marker for hematopoietic stem cells. Ann N Y Acad Sci 996: 222–226.

    Article  CAS  PubMed  Google Scholar 

  • Felding-Habermann B . (2003). Integrin adhesion receptors in tumor metastasis. Clin Exp Metastasis 20: 203–213.

    Article  CAS  PubMed  Google Scholar 

  • Hanada M, Tanaka K, Matsumoto Y, Nakatani F, Sakimura R, Matsunobu T et al. (2005). Focal adhesion kinase is activated in invading fibrosarcoma cells and regulates metastasis. Clin Exp Metastasis 22: 485–494.

    Article  CAS  PubMed  Google Scholar 

  • Hirohashi S, Kanai Y . (2003). Cell adhesion system and human cancer morphogenesis. Cancer Sci 94: 575–581.

    Article  CAS  PubMed  Google Scholar 

  • Hood JD, Cheresh DA . (2002). Role of integrins in cell invasion and migration. Nat Rev Cancer 2: 91–100.

    Article  PubMed  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 

  • Ikeda JI, Morii E, Kimura H, Tomita Y, Takakuwa T, Hasegawa JI et al. (2006). Epigenetic regulation of the expression of the novel stem cell marker CDCP1 in cancer cells. J Pathol 210: 75–84.

    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 

  • Ji L, Minna JD, Roth JA . (2005). 3p21.3 tumor suppressor cluster: prospects for translational applications. Future Oncol 1: 79–92.

    Article  CAS  PubMed  Google Scholar 

  • Kessenbrock K, Plaks V, Werb Z . (2010). Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141: 52–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lahlou H, Sanguin-Gendreau V, Zuo D, Cardiff RD, McLean GW, Frame MC et al. (2007). Mammary epithelial-specific disruption of the focal adhesion kinase blocks mammary tumor progression. Proc Natl Acad Sci USA 104: 20302–20307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mamat S, Ikeda J, Enomoto T, Ueda Y, Rahadiani N, Tian T et al. (2010). Prognostic significance of CUB domain containing protein expression in endometrioid adenocarcinoma. Oncol Rep 23: 1221–1227.

    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 

  • Pietras K, Ostman A . (2010). Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res 316: 1324–1331.

    Article  CAS  PubMed  Google Scholar 

  • Provenzano PP, Inman DR, Eliceiri KW, Beggs HE, Keely PJ . (2008). Mammary epithelial-specific disruption of focal adhesion kinase retards tumor formation and metastasis in a transgenic mouse model of human breast cancer. Am J Pathol 173: 1551–1565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramsay AG, Marshall JF, Hart IR . (2007). Integrin trafficking and its role in cancer metastasis. Cancer Metastasis Rev 26: 567–578.

    Article  CAS  PubMed  Google Scholar 

  • Rathinam R, Alahari SK . (2010). Important role of integrins in the cancer biology. Cancer Metastasis Rev 29: 223–237.

    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 

  • Shibue T, Weinberg RA . (2009). Integrin beta1-focal adhesion kinase signaling directs the proliferation of metastatic cancer cells disseminated in the lungs. Proc Natl Acad Sci USA 106: 10290–10295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siva AC, Wild MA, Kirkland RE, Nolan MJ, Lin B, Maruyama T et al. (2008). Targeting CUB domain-containing protein 1 with a monoclonal antibody inhibits metastasis in a prostate cancer model. Cancer Res 68: 3759–3766.

    Article  CAS  PubMed  Google Scholar 

  • Spassov DS, Ahuja D, Wong CH, Moasser MM . (2011a). The structural features of Trask that mediate its anti-adhesive functions. PLoS One 6: e19154.

    Article  CAS  PubMed  PubMed Central  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. (2011b). 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 

  • Spiegelberg BD, Hamm HE . (2007). Roles of G-protein-coupled receptor signaling in cancer biology and gene transcription. Curr Opin Genet Dev 17: 40–44.

    Article  CAS  PubMed  Google Scholar 

  • Srinivasan DM, Kapoor M, Kojima F, Crofford LJ . (2005). Growth factor receptors: implications in tumor biology. Curr Opin Investig Drugs 6: 1246–1249.

    CAS  PubMed  Google Scholar 

  • Sun H, Pisle S, Gardner ER, Figg WD . (2010). Bioluminescent imaging study: FAK inhibitor, PF-562,271, preclinical study in PC3M-luc-C6 local implant and metastasis xenograft models. Cancer Biol Ther 10: 38–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang J, Wu YM, Zhao P, Yang XM, Jiang JL, Chen ZN . (2008). Overexpression of HAb18G/CD147 promotes invasion and metastasis via alpha3beta1 integrin mediated FAK-paxillin and FAK-PI3K-Ca2+ pathways. Cell Mol Life Sci 65: 2933–2942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tlsty TD, Coussens LM . (2006). Tumor stroma and regulation of cancer development. Annu Rev Pathol 1: 119–150.

    Article  CAS  PubMed  Google Scholar 

  • Trimmer C, Whitaker-Menezes D, Bonuccelli G, Milliman JN, Daumer KM, Aplin AE et al. (2010). CAV1 inhibits metastatic potential in melanomas through suppression of the integrin/Src/FAK signaling pathway. Cancer Res 70: 7489–7499.

    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 

  • Van Nimwegen MJ, Verkoeijen S, van Buren L, Burg D, van de Water B . (2005). Requirement for focal adhesion kinase in the early phase of mammary adenocarcinoma lung metastasis formation. Cancer Res 65: 4698–4706.

    Article  CAS  PubMed  Google Scholar 

  • Walsh C, Tanjoni I, Uryu S, Tomar A, Nam JO, Luo H et al. (2010). Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. Cancer Biol Ther 9: 778–790.

    Article  CAS  PubMed  Google Scholar 

  • Wistuba II, Behrens C, Virmani AK, Mele G, Milchgrub S, Girard L et al. (2000). High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res 60: 1949–1960.

    CAS  PubMed  Google Scholar 

  • Wong CH, Baehner FL, Spassov DS, Ahuja D, Wang D, Hann B et al. (2009). Phosphorylation of the SRC epithelial substrate Trask is tightly regulated in normal epithelia but widespread in many human epithelial cancers. Clin Cancer Res 15: 2311–2322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was funded by the National Institutes of Health CA113952 (MMM). DS is funded by a Susan G Komen for the Cure Postdoctoral Fellowship. CHW is funded by a California Breast Cancer Research Program Postdoctoral Fellowship. We wish to thank Michael McManus and the UCSF Sandler Lentiviral RNAi core facility. We acknowledge the use of core facilities of the UCSF Helen Diller Family Comprehensive Cancer Center, including the Preclinical Therapeutics Core, the immunohistochemistry core and the mouse pathology core.

Author information

Authors and Affiliations

  1. Department of Medicine, University of California, San Francisco, CA, USA

    D S Spassov, C H Wong, G Harris, S McDonough & M M Moasser

  2. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA

    D S Spassov, C H Wong, P Phojanakong, D Wang, B Hann & M M Moasser

  3. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

    A V Bazarov & P Yaswen

  4. Department of Pathology, University of California, San Francisco, CA, USA

    E Khanafshar

Authors
  1. D S Spassov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C H Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S McDonough
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P Phojanakong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B Hann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A V Bazarov
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P Yaswen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. E Khanafshar
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M M Moasser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M M Moasser.

Ethics declarations

Competing interests

The authors declare no conflict to interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spassov, D., Wong, C., Harris, G. et al. A tumor-suppressing function in the epithelial adhesion protein Trask. Oncogene 31, 419–431 (2012). https://doi.org/10.1038/onc.2011.246

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.246

Keywords

This article is cited by

Search

Advanced search

Quick links