The interaction between caveolin-1 and Rho-GTPases promotes metastasis by controlling the expression of alpha5-integrin and the activation of Src, Ras and Erk

E. Arpaia, H. Blaser, M. Quintela-Fandino, G. Duncan, H. S. Leong, A. Ablack, S. C. Nambiar, Evan Lind, J. Silvester, C. K. Fleming, A. Rufini, M. W. Tusche, A. Brüstle, P. S. Ohashi, J. D. Lewis, T. W. Mak

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Proteins containing a caveolin-binding domain (CBD), such as the Rho-GTPases, can interact with caveolin-1 (Cav1) through its caveolin scaffold domain. Rho-GTPases are important regulators of p130 Cas, which is crucial for both normal cell migration and Src kinase-mediated metastasis of cancer cells. However, although Rho-GTPases (particularly RhoC) and Cav1 have been linked to cancer progression and metastasis, the underlying molecular mechanisms are largely unknown. To investigate the function of Cav1-Rho-GTPase interaction in metastasis, we disrupted Cav1-Rho-GTPase binding in melanoma and mammary epithelial tumor cells by overexpressing CBD, and examined the loss-of-function of RhoC in metastatic cancer cells. Cancer cells overexpressing CBD or lacking RhoC had reduced p130 Cas phosphorylation and Rac1 activation, resulting in an inhibition of migration and invasion in vitro. The activity of Src and the activation of its downstream targets FAK, Pyk2, Ras and extracellular signal-regulated kinase (Erk)1/2 were also impaired. A reduction in α5-integrin expression, which is required for binding to fibronectin and thus cell migration and survival, was observed in CBD-expressing cells and cells lacking RhoC. As a result of these defects, CBD-expressing melanoma cells had a reduced ability to metastasize in recipient mice, and impaired extravasation and survival in secondary sites in chicken embryos. Our data indicate that interaction between Cav1 and Rho-GTPases (most likely RhoC but not RhoA) promotes metastasis by stimulating α5-integrin expression and regulating the Src-dependent activation of p130 Cas/Rac1, FAK/Pyk2 and Ras/Erk1/2 signaling cascades.

Original languageEnglish (US)
Pages (from-to)884-896
Number of pages13
JournalOncogene
Volume31
Issue number7
DOIs
StatePublished - Feb 16 2012
Externally publishedYes

Fingerprint

Integrin alpha5
Caveolins
Caveolin 1
rho GTP-Binding Proteins
Extracellular Signal-Regulated MAP Kinases
Neoplasm Metastasis
Integrins
Cell Movement
Melanoma
Neoplasms
Mitogen-Activated Protein Kinase 3
src-Family Kinases
Mitogen-Activated Protein Kinase 1
Fibronectins
Chickens
Cell Survival
Embryonic Structures
Epithelial Cells
Phosphorylation
Breast Neoplasms

Keywords

  • alpha5-integrin
  • cancer
  • caveolin-1
  • intravital microscopy
  • Rho-GTPase
  • Src

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

The interaction between caveolin-1 and Rho-GTPases promotes metastasis by controlling the expression of alpha5-integrin and the activation of Src, Ras and Erk. / Arpaia, E.; Blaser, H.; Quintela-Fandino, M.; Duncan, G.; Leong, H. S.; Ablack, A.; Nambiar, S. C.; Lind, Evan; Silvester, J.; Fleming, C. K.; Rufini, A.; Tusche, M. W.; Brüstle, A.; Ohashi, P. S.; Lewis, J. D.; Mak, T. W.

In: Oncogene, Vol. 31, No. 7, 16.02.2012, p. 884-896.

Research output: Contribution to journalArticle

Arpaia, E, Blaser, H, Quintela-Fandino, M, Duncan, G, Leong, HS, Ablack, A, Nambiar, SC, Lind, E, Silvester, J, Fleming, CK, Rufini, A, Tusche, MW, Brüstle, A, Ohashi, PS, Lewis, JD & Mak, TW 2012, 'The interaction between caveolin-1 and Rho-GTPases promotes metastasis by controlling the expression of alpha5-integrin and the activation of Src, Ras and Erk', Oncogene, vol. 31, no. 7, pp. 884-896. https://doi.org/10.1038/onc.2011.288
Arpaia, E. ; Blaser, H. ; Quintela-Fandino, M. ; Duncan, G. ; Leong, H. S. ; Ablack, A. ; Nambiar, S. C. ; Lind, Evan ; Silvester, J. ; Fleming, C. K. ; Rufini, A. ; Tusche, M. W. ; Brüstle, A. ; Ohashi, P. S. ; Lewis, J. D. ; Mak, T. W. / The interaction between caveolin-1 and Rho-GTPases promotes metastasis by controlling the expression of alpha5-integrin and the activation of Src, Ras and Erk. In: Oncogene. 2012 ; Vol. 31, No. 7. pp. 884-896.
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AU - Duncan, G.

AU - Leong, H. S.

AU - Ablack, A.

AU - Nambiar, S. C.

AU - Lind, Evan

AU - Silvester, J.

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AU - Rufini, A.

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