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Melanoma chondroitin sulphate proteoglycan regulates cell spreading through Cdc42, Ack-1 and p130cas

Nature Cell Biology volume 1, pages 507–513 (1999)Cite this article

Abstract

Melanoma chondroitin sulphate proteoglycan (MCSP) is a cell-surface antigen that has been implicated in the growth and invasion of melanoma tumours. Although this antigen is expressed early in melanoma progression, its biological function is unknown. MCSP can stimulate the integrin-α4β1-mediated adhesion and spreading of melanoma cells. Here we show that stimulated MCSP recruits tyrosine-phosphorylated p130cas, an adaptor protein important in tumour cell motility and invasion. MCSP stimulation also results in a pronounced activation and recruitment of the Rho-family GTPase Cdc42. MCSP-induced spreading of melanoma cells is dependent upon active Cdc42, a Cdc42-associated tyrosine kinase (Ack-1) and tyrosine phosphorylation of p130cas. Furthermore, vectors inhibiting Ack-1 or Cdc42 expression and/or function abrogate MCSP-induced tyrosine phosphorylation and recruitment of p130cas. Our findings indicate that MCSP may modify tumour growth or invasion by a unique signal-transduction pathway that links Cdc42 activation to downstream tyrosine phosphorylation and subsequent cytoskeletal reorganization.

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Figure 1: MCSP clustering induces tyrosine phoshorylation of p130cas.
Figure 2: MCSP-induced α4β1-integrin-dependent cell spreading involves p130cas signalling.
Figure 3: Activated Cdc42 associates with MCSP and induces spreading of melanoma cells.
Figure 4: Cdc42 mediates MCSP-induced p130cas recruitment and tyrosine phosphorylation.
Figure 5: Ack-1 kinase activity is associated with MCSP.
Figure 6: Ack-1 kinase induces spreading of melanoma cells and tyrosine phosphorylation of p130cas.

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Acknowledgements

We thank Y. Shimizu for valuable discussions. This work was supported by grant CA21463 from the NIH (to L.T.F.). L.T.F. is a recipient of an Allen-Pardee professorship in cancer biology.

Correspondence and requests for materials should be addressed to J.B.M.

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, 55455, Minnesota, USA

    Kathryn M. Eisenmann, James B. McCarthy, Melanie A. Simpson, Leo T. Furcht & Joji Iida

  2. Biomedical Engineering Institute, University of Minnesota , , Minneapolis, 55455, Minnesota, USA

    James B. McCarthy & Leo T. Furcht

  3. Cancer Center, University of Minnesota, Minneapolis, 55455, Minnesota, USA

    James B. McCarthy & Joji Iida

  4. Department of Molecular Medicine, Cornell University, Ithaca, 14853, New York, USA

    Jun-Lin Guan

  5. Department of Pharmacology, University of Wisconsin, Madison, 53706, Wisconsin, USA

    Patricia J. Keely

  6. Department of Cancer Immunology and AIDS, Harvard Medical School, Boston, 02115, , Massachusetts, USA

    Kouichi Tachibana

  7. Institute of Neurology, London, WC1N 1PJ, UK

    Louis Lim

  8. Institute of Molecular and Cell Biology, National University of Singapore, 15 Lower Kent Ridge Road, 119076, Singapore

    Ed Manser

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Eisenmann, K., McCarthy, J., Simpson, M. et al. Melanoma chondroitin sulphate proteoglycan regulates cell spreading through Cdc42, Ack-1 and p130cas. Nat Cell Biol 1, 507–513 (1999). https://doi.org/10.1038/70302

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