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Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

Oncogene volume 25, pages 2367–2378 (2006)Cite this article

Abstract

KAI1/CD82, a tetraspanin protein, was first identified as a metastasis suppressor in prostate cancer. How loss of CD82 expression promotes cancer metastasis is unknown. Restoration of CD82 expression to physiological levels in the metastatic prostate cell line PC3 inhibits integrin-mediated cell migration and invasion, but does not affect integrin expression. Integrin-dependent activation of the receptor kinase c-Met is dramatically reduced in CD82-expressing cells, as is c-Met activation by its ligand HGF/SF. CD82 expression also reduced integrin-induced activation and phosphorylation of the cytoplasmic tyrosine kinase Src, and its downstream substrates p130Cas and FAK Y861. Inhibition of c-Met expression or Src kinase function reduced matrigel invasion of PC3 cells to the same extent as CD82 expression. These data indicate that CD82 functions to suppress integrin-induced invasion by regulating signaling to c-Met and Src kinases, and suggests that CD82 loss may promote metastasis by removing a negative regulator of c-Met and Src signaling.

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Acknowledgements

We thank Dr Eric Rubinstein for his generous gift of the anti-CD82 (TS82) antibody, Dr Beatrice Knudsen for her beautiful primary prostate epithelial cells, and Dr Kurt Cannon for the CD82 cDNA construct. We thank Veronique Schulz, Matt Van Brocklin, and Dr Jim Resau for their technical support. Funding for this project for both CKM and SCS was provided by the Department of Defense Prostate Cancer Research Program of the Office of Congressionally Directed Medical Research Programs and by the generous gifts of the Van Andel Research Institute.

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  1. Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI, USA

    S C Sridhar & C K Miranti

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Sridhar, S., Miranti, C. Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases. Oncogene 25, 2367–2378 (2006). https://doi.org/10.1038/sj.onc.1209269

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