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Regulation of inside-out β1-integrin activation by CDCP1

Oncogene volume 37, pages 2817–2836 (2018)Cite this article

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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.

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Acknowledgements

We heartily acknowledge Wen-Chin Huang for assistance in animal surgery, L. Chung for support in in vivo experiments, and to C. Pospisil for cloning PKCδ mutant with inactive kinase into vector. We thank the patients and their families, Robert Vessella, Eva Corey, Celestia Higano, Bruce Montgomery, Peter Nelson, Paul Lange, Martine Roudier, and Lawrence True for their contributions to the University of Washington Medical Center Prostate Cancer Donor Rapid Autopsy Program supported by funding by the Pacific Northwest Prostate Cancer SPORE (P50CA97186) and the Richard M. LUCAS Foundation. We are thankful to Jennifer Kitchel and the Biobank and Translational Research Core at Cedars-Sinai Medical Center for xenograft embedding, tissue processing, and IHC staining. This work was supported by Department of Defense Synergistic Idea Development Award W81XWH-08-1-0268 and start-up funding from Cedars-Sinai Medical Center.

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Authors and Affiliations

  1. Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Sara G. Pollan, Fangjin Huang, C. Y. Chu, Neil A. Bhowmick, Sungyong You, Michael R. Freeman & Beatrice S. Knudsen

  2. University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA

    Jamie M. Sperger & Joshua M. Lang

  3. University of Washington, Seattle, WA, 98195, USA

    Colm Morrissey

  4. University of Arizona Cancer Center, Tucson, AZ, 85704, USA

    Anne E. Cress

  5. University of California San Francisco, San Francisco, CA, 94143, USA

    Danislav S. Spassov & Mark M. Moasser

  6. Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

    William G. Carter

  7. Purdue University, West Lafayette, IN, 47907, USA

    Shakti Ranjan Satapathy & Kavita Shah

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  1. Sara G. Pollan
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Contributions

SP performed experiments and wrote the paper. FH performed computational experiments found in Fig. 1A, B, D. JS and JL contributed the qPCR analysis of CTCs found in Fig. 1C. CM provided tissues from rapid autopsies of patients with metastatic prostate cancers. AC provided scientific input on regulation of β1-integrin. NB provided scientific input on TGF-beta 1 in prostate cancer. DS and MM generated and contributed the short hairpins for knockdown of CDCP1. WC independently discovered CDCP1 and initiated the project. SRS performed CDK5 kinase assays found in Fig. 6C and Supplementary Fig. 6A. KS contributed prediction models of protein phosphorylation. BK provided the conceptual framework and wrote the paper.

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Correspondence to Beatrice S. Knudsen.

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Pollan, S.G., Huang, F., Sperger, J.M. et al. Regulation of inside-out β1-integrin activation by CDCP1. Oncogene 37, 2817–2836 (2018). https://doi.org/10.1038/s41388-018-0142-2

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