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Novel protease mediated mechanisms promote the spread of cancer cells via the blood circulation
Author(s) -
Hooper John,
Yaowu He,
Casar Berta,
Ying Dong,
Wortmann Andreas,
Adams Mark,
Clements Judith,
Quigley James
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.600.1
Subject(s) - proteases , microbiology and biotechnology , proto oncogene tyrosine protein kinase src , cancer cell , anoikis , cancer research , metastasis , effector , biology , signal transduction , cancer , chemistry , biochemistry , enzyme , genetics
Although the dysfunctional activities of proteases in cancer metastasis have been recognised for some time, the particular mechanisms mediating the roles of these enzymes in the spread of cancer remain poorly defined. Recently we have demonstrated that signals initiated by proteolytic cleavage of cell surface receptors can initiate metastasis promoting responses. One of these receptors is the cell surface glycoprotein CUB domain containing protein 1 (CDCP1). Our data indicate that CDCP1 is cleaved at the cell surface in vitro and in vivo by serine proteases thereby initiating intracellular signalling cascades involving activation and docking to CDCP1 of the kinases Src and PKCδ and downstream activation of Akt. Interestingly, we have shown that this cascade protects cancer cells as they disseminate via blood vessels in vivo and we have identified proteases initiating this protection in model systems. Our findings further demonstrate roles for CDCP1 in cell migration in vitro including its competition as a Src substrate with a critical mediator of cell adhesion, FAK, and its role in migration induced by EGFR signalling. Targeting CDCP1 and its signalling effectors may be a rational approach to treat cancer patients at risk of recurrent disease. Support: Wesley Research Institute, Australian Research Council, Cancer Council Queensland, National Health and Medical Research Council of Australia