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Regulation of inside-out β1-integrin activation by CDCP1

Authors :
Anne E. Cress
Sungyong You
Beatrice S. Knudsen
Joshua M. Lang
Danislav S. Spassov
Kavita Shah
Michael R. Freeman
Sara Pollan
Jamie M. Sperger
Colm Morrissey
Fangjin Huang
Shakti Ranjan Satapathy
William G. Carter
Chia-Yi Chu
Neil A. Bhowmick
Mark M. Moasser
Source :
Oncogene. 37:2817-2836
Publication Year :
2018
Publisher :
Springer Science and Business Media LLC, 2018.

Abstract

Tumor metastasis depends on the dynamic regulation of cell adhesion through β1-integrin. The Cub-Domain Containing Protein-1, CDCP1, is a transmembrane glycoprotein which regulates cell adhesion. Overexpression and loss of CDCP1 have been observed in the same cancer types to promote metastatic progression. Here, we demonstrate reduced CDCP1 expression in high-grade, primary prostate cancers, circulating tumor cells and tumor metastases of patients with castrate-resistant prostate cancer. CDCP1 is expressed in epithelial and not mesenchymal cells, and its cell surface and mRNA expression declines upon stimulation with TGFβ1 and epithelial-to-mesenchymal transition. Silencing of CDCP1 in DU145 and PC3 cells resulted in 3.4-fold higher proliferation of non-adherent cells and 4.4-fold greater anchorage independent growth. CDCP1-silenced tumors grew in 100% of mice, compared to 30% growth of CDCP1-expressing tumors. After CDCP1 silencing, cell adhesion and migration diminished 2.1-fold, caused by loss of inside-out activation of β1-integrin. We determined that the loss of CDCP1 reduces CDK5 kinase activity due to the phosphorylation of its regulatory subunit, CDK5R1/p35, by c-SRC on Y234. This generates a binding site for the C2 domain of PKCδ, which in turn phosphorylates CDK5 on T77. The resulting dissociation of the CDK5R1/CDK5 complex abolishes the activity of CDK5. Mutations of CDK5-T77 and CDK5R1-Y234 phosphorylation sites re-establish the CDK5/CDKR1 complex and the inside-out activity of β1-integrin. Altogether, we discovered a new mechanism of regulation of CDK5 through loss of CDCP1, which dynamically regulates β1-integrin in non-adherent cells and which may promote vascular dissemination in patients with advanced prostate cancer.

Details

ISSN :
14765594 and 09509232
Volume :
37
Database :
OpenAIRE
Journal :
Oncogene
Accession number :
edsair.doi.dedup.....5165dbd8d54190c1033a9a5b3fc21e39
Full Text :
https://doi.org/10.1038/s41388-018-0142-2