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The Rsu-1-PINCH1-ILK complex is regulated by Ras activation in tumor cells

Gerard W Dougherty1, Cynthia Jose, Mario Gimona

  • 1Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, Via Nazionale 8a, I-66030 Santa Maria Imbaro, Italy.

European Journal of Cell Biology
|April 26, 2008
PubMed

Insights

Ras transformation enhances cell migration by altering integrin signaling. Ras suppressor Rsu-1 normally inhibits migration by stabilizing the IPP complex, but Ras activation disrupts this by affecting Rsu-1 splicing and IPP complex association.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Ras transformation is linked to increased cell migration via integrin signaling in tumorigenesis.
  • The Ras suppressor Rsu-1 interacts with the integrin-linked kinase (ILK), PINCH-1, and parvin (IPP) complex.
  • Understanding the Rsu-1-IPP complex role in tumorigenesis is crucial as ILK and PINCH1 are elevated in tumors, and Rsu-1 inhibits tumorigenesis.

Purpose of the Study:

  • To investigate the role of Rsu-1 and its alternatively spliced isoform in Ras-mediated cell migration.
  • To define how Ras transformation affects the Rsu-1 interaction with the IPP complex.
  • To elucidate the mechanism by which Rsu-1 influences cell migration and tumorigenesis.

Main Methods:

  • Detection of alternatively spliced Rsu-1 RNA and its corresponding truncated p29 protein in human tumor cell lines.
  • Inhibitor studies to assess Mek-ERK pathway regulation of truncated Rsu-1.
  • Co-localization and co-immunoprecipitation assays to study Rsu-1 and IPP complex interactions in transformed and non-transformed cells.
  • In vitro studies using a human breast cancer cell line involving depletion of full-length and truncated Rsu-1 proteins.

Main Results:

  • A truncated Rsu-1 protein (p29) correlating with alternatively spliced Rsu-1 RNA was detected in human tumor cells with activated Ras.
  • The Mek-ERK pathway was found to regulate the expression of truncated Rsu-1.
  • Rsu-1 co-localizes with ILK at focal contacts and associates with the ILK-PINCH1 complex in non-transformed cells, but this association is reduced upon Ras transformation.
  • Depletion of full-length Rsu-1 enhanced migration and Rac-GTP levels, while depletion of p29 Rsu-1 inhibited migration in a breast cancer cell line.

Conclusions:

  • Rsu-1 inhibits cell migration by stabilizing the IPP adhesion complex.
  • Ras activation disrupts Rsu-1's inhibitory function by modulating Rsu-1 splicing and its association with the IPP complex.
  • Rsu-1 acts as a crucial link between the Ras pathway and the IPP complex, influencing cell attachment signaling in malignancy.

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