CUB domain-containing protein 1 (CDCP1) is a protein that in humans is encoded by the CDCP1gene.[1][2] CDCP1 has also been designated as CD318 (cluster of differentiation 318) and Trask (Transmembrane and associated with src kinases). Alternatively spliced transcript variants encoding distinct isoforms have been reported.[2]
CDCP1/Trask is not important for the development of the mouse.[3] Adult mice lacking CDCP1 do not exhibit gross morphologic, reproductive or behavioral abnormalities compared with wild-type mice, and histologic examination of multiple organ systems has shown no significant pathology and no observed histologic differences.[3] CDCP1 is a ligand for CD6, a receptor molecule expressed on certain T-cells and may play a role in their migration and chemotaxis. As such CDCP1 may contribute to autoimmune diseases such as encephalomyelitis, multiple sclerosis and inflammatory arthritis.[4]
CDCP1 is a 140 kD transmembrane glycoprotein with a large extracellular domain (ECD) containing two CUB domains, and a smaller intracellular domain (ICD). CDCP1 is cleaved by serine proteases at the extracellular domain next to Arg368 to generate a truncated molecule of 80 kDa size.[5] Different cell lines express different amounts of p140 and p80, depending on the activity of endogenous serine proteases. In vivo, CDCP1 is not cleaved during normal physiological circumstances, but its cleavage can be induced during tumorigenesis or tissue injury.[3]
The intracellular domain of CDCP1 contains five tyrosine residues - Y707, Y734, Y743, Y762 and Y806. Phosphorylation of CDCP1 is exclusively mediated by Src kinases and depends on the adherence state of the cells.[6][7] The tyrosine phosphorylation of CDCP1 in cultured cells occurs when cells are induced to detach by trypsin or EDTA, or seen spontaneously during mitotic detachment. The loss of anchorage or cellular detachment is associated with the phosphorylation of CDCP1 as well as the concomitant dephosphorylation of focal adhesion proteins, consistent with the dismantling of focal adhesions.[7] Contrary, during cellular attachment CDCP1 is dephosphorylated, allowing the phosphorylation of focal adhesion proteins. The anti-adhesion and anti-migratory functions of CDCP1 are mediated through negative regulation on integrin receptors.[8]
Clinical significance
The phosphorylation of CDCP1 is seen in many cancers, including some pre-invasive cancers as well as in invasive tumors and in tumor metastases.[9]
References
↑Scherl-Mostageer M, Sommergruber W, Abseher R, Hauptmann R, Ambros P, Schweifer N (July 2001). "Identification of a novel gene, CDCP1, overexpressed in human colorectal cancer". Oncogene. 20 (32): 4402–8. doi:10.1038/sj.onc.1204566. PMID11466621.
↑Wortmann A, He Y, Deryugina EI, Quigley JP, Hooper JD (July 2009). "The cell surface glycoprotein CDCP1 in cancer--insights, opportunities, and challenges". IUBMB Life. 61 (7): 723–30. doi:10.1002/iub.198. PMID19514048.
Hooper JD, Zijlstra A, Aimes RT, Liang H, Claassen GF, Tarin D, Testa JE, Quigley JP (March 2003). "Subtractive immunization using highly metastatic human tumor cells identifies SIMA135/CDCP1, a 135 kDa cell surface phosphorylated glycoprotein antigen". Oncogene. 22 (12): 1783–94. doi:10.1038/sj.onc.1206220. PMID12660814.
Conze T, Lammers R, Kuci S, Scherl-Mostageer M, Schweifer N, Kanz L, Buhring HJ (May 2003). "CDCP1 is a novel marker for hematopoietic stem cells". Annals of the New York Academy of Sciences. 996 (1): 222–6. doi:10.1111/j.1749-6632.2003.tb03249.x. PMID12799299.
Brown TA, Yang TM, Zaitsevskaia T, Xia Y, Dunn CA, Sigle RO, Knudsen B, Carter WG (April 2004). "Adhesion or plasmin regulates tyrosine phosphorylation of a novel membrane glycoprotein p80/gp140/CUB domain-containing protein 1 in epithelia". The Journal of Biological Chemistry. 279 (15): 14772–83. doi:10.1074/jbc.M309678200. PMID14739293.
Bühring HJ, Kuçi S, Conze T, Rathke G, Bartolović K, Grünebach F, Scherl-Mostageer M, Brümmendorf TH, Schweifer N, Lammers R (2005). "CDCP1 identifies a broad spectrum of normal and malignant stem/progenitor cell subsets of hematopoietic and nonhematopoietic origin". Stem Cells. 22 (3): 334–43. doi:10.1634/stemcells.22-3-334. PMID15153610.
Benes CH, Wu N, Elia AE, Dharia T, Cantley LC, Soltoff SP (April 2005). "The C2 domain of PKCdelta is a phosphotyrosine binding domain". Cell. 121 (2): 271–80. doi:10.1016/j.cell.2005.02.019. PMID15851033.
André M, Le Caer JP, Greco C, Planchon S, El Nemer W, Boucheix C, Rubinstein E, Chamot-Rooke J, Le Naour F (March 2006). "Proteomic analysis of the tetraspanin web using LC-ESI-MS/MS and MALDI-FTICR-MS". Proteomics. 6 (5): 1437–49. doi:10.1002/pmic.200500180. PMID16404722.
Kimura H, Morii E, Ikeda JI, Ezoe S, Xu JX, Nakamichi N, Tomita Y, Shibayama H, Kanakura Y, Aozasa K (September 2006). "Role of DNA methylation for expression of novel stem cell marker CDCP1 in hematopoietic cells". Leukemia. 20 (9): 1551–6. doi:10.1038/sj.leu.2404312. PMID16926850.
Perry SE, Robinson P, Melcher A, Quirke P, Bühring HJ, Cook GP, Blair GE (March 2007). "Expression of the CUB domain containing protein 1 (CDCP1) gene in colorectal tumour cells". FEBS Letters. 581 (6): 1137–42. doi:10.1016/j.febslet.2007.02.025. PMID17335815.
