Regulation of inside-out β1-integrin activation by CDCP1

Sara G. Pollan, Fangjin Huang, Jamie M. Sperger, Joshua M. Lang, Colm Morrissey, Anne E Cress, C. Y. Chu, Neil A. Bhowmick, Sungyong You, Michael R. Freeman, Danislav S. Spassov, Mark M. Moasser, William G. Carter, Shakti Ranjan Satapathy, Kavita Shah, Beatrice S. Knudsen

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-20
Number of pages20
JournalOncogene
DOIs
StateAccepted/In press - Mar 7 2018

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Integrins
Cell Adhesion
Prostatic Neoplasms
Neoplasms
Phosphorylation
Neoplasm Metastasis
Circulating Neoplastic Cells
Epithelial-Mesenchymal Transition
Growth
Cell Movement
Blood Vessels
Glycoproteins
Phosphotransferases
Binding Sites
Messenger RNA
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Pollan, S. G., Huang, F., Sperger, J. M., Lang, J. M., Morrissey, C., Cress, A. E., ... Knudsen, B. S. (Accepted/In press). Regulation of inside-out β1-integrin activation by CDCP1. Oncogene, 1-20. https://doi.org/10.1038/s41388-018-0142-2

Regulation of inside-out β1-integrin activation by CDCP1. / Pollan, Sara G.; Huang, Fangjin; Sperger, Jamie M.; Lang, Joshua M.; Morrissey, Colm; Cress, Anne E; Chu, C. Y.; Bhowmick, Neil A.; You, Sungyong; Freeman, Michael R.; Spassov, Danislav S.; Moasser, Mark M.; Carter, William G.; Satapathy, Shakti Ranjan; Shah, Kavita; Knudsen, Beatrice S.

In: Oncogene, 07.03.2018, p. 1-20.

Research output: Contribution to journalArticle

Pollan, SG, Huang, F, Sperger, JM, Lang, JM, Morrissey, C, Cress, AE, Chu, CY, Bhowmick, NA, You, S, Freeman, MR, Spassov, DS, Moasser, MM, Carter, WG, Satapathy, SR, Shah, K & Knudsen, BS 2018, 'Regulation of inside-out β1-integrin activation by CDCP1', Oncogene, pp. 1-20. https://doi.org/10.1038/s41388-018-0142-2
Pollan SG, Huang F, Sperger JM, Lang JM, Morrissey C, Cress AE et al. Regulation of inside-out β1-integrin activation by CDCP1. Oncogene. 2018 Mar 7;1-20. https://doi.org/10.1038/s41388-018-0142-2
Pollan, Sara G. ; Huang, Fangjin ; Sperger, Jamie M. ; Lang, Joshua M. ; Morrissey, Colm ; Cress, Anne E ; Chu, C. Y. ; Bhowmick, Neil A. ; You, Sungyong ; Freeman, Michael R. ; Spassov, Danislav S. ; Moasser, Mark M. ; Carter, William G. ; Satapathy, Shakti Ranjan ; Shah, Kavita ; Knudsen, Beatrice S. / Regulation of inside-out β1-integrin activation by CDCP1. In: Oncogene. 2018 ; pp. 1-20.
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AU - Morrissey, Colm

AU - Cress, Anne E

AU - Chu, C. Y.

AU - Bhowmick, Neil A.

AU - You, Sungyong

AU - Freeman, Michael R.

AU - Spassov, Danislav S.

AU - Moasser, Mark M.

AU - Carter, William G.

AU - Satapathy, Shakti Ranjan

AU - Shah, Kavita

AU - Knudsen, Beatrice S.

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