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Molecular Pharmacology

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Research ArticleArticle

Cooperative Role of Caveolin-1 and C-Terminal Src Kinase Binding Protein in C-Terminal Src Kinase-Mediated Negative Regulation of c-Src

Aaron T. Place, Zhenlong Chen, Farnaz R. Bakhshi, Guoquan Liu, John P. O'Bryan and Richard D. Minshall
Molecular Pharmacology October 2011, 80 (4) 665-672; DOI: https://doi.org/10.1124/mol.111.073957
Aaron T. Place
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Zhenlong Chen
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Farnaz R. Bakhshi
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Guoquan Liu
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John P. O'Bryan
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Richard D. Minshall
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Abstract

In the present study, we assessed the cooperative roles of C-terminal Src kinase (Csk) binding protein (Cbp) and Caveolin-1 (Cav-1) in the mechanism of Src family tyrosine kinase (SFK) inhibition by Csk. SFKs are inactivated by phosphorylation of their C-terminal tyrosine by Csk. Whereas SFKs are membrane-associated, Csk is a cytoplasmic protein and therefore requires membrane adaptors such as Cbp or Cav-1 for recruitment to the plasma membrane to mediate SFK inhibition. To determine the specific role of Cav-1 and Cbp in SFK inhibition, we measured c-Src activity in the absence of each membrane adaptor. It is noteworthy that in lungs and fibroblasts from Cav-1(−/−) mice, we observed increased expression of Cbp compared with wild-type (WT) controls. However, both c-Src activity and Csk localization at the membrane were similar between Cav-1(−/−) fibroblasts and WT cells. Likewise, Cbp depletion by small interfering RNA (siRNA) treatment of WT cells had no effect on basal c-Src activity, but it increased the phosphorylation state of Cav-1. Immunoprecipitation then confirmed increased association of Csk with phosphomimicking Cav-1. Knockdown of Cbp by siRNA in Cav-1(−/−) cells revealed increased basal c-Src activity, and re-expression of WT Cav-1 in the same cells reduced basal c-Src activity. Taken together, these results indicate that Cav-1 and Cbp cooperatively regulate c-Src activity by recruiting Csk to the membrane where it phosphorylates c-Src inhibitory tyrosine 529. Furthermore, when either Cav-1 or Cbp expression is reduced or absent, there is a compensatory increase in the phosphorylation state or expression level of the other membrane-associated Csk adaptor to maintain SFK inhibition.

Footnotes

  • This research was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants R01-HL71626, P01-HL60678]; and the American Heart Association Midwest Affiliate [Grant 0910026G].

  • This article is based on a thesis submitted in partial fulfillment of the requirements for a doctoral degree: Place AT (2011) Molecular mechanism of Src regulation by Csk, SHP-2, Cbp, and caveolin-1. Ph.D. thesis, Department of Pharmacology, University of Illinois, Chicago, IL.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.073957.

  • ABBREVIATIONS:

    SFK
    Src family kinase
    Csk
    C-terminal Src kinase
    Cbp
    Csk-binding protein
    MF
    mouse fibroblasts
    SH
    Src homology
    WT
    wild type
    siRNA
    small interfering RNA
    PAGE
    polyacrylamide gel electrophoresis
    RIPA
    radioimmunoprecipitation assay
    PMSF
    phenylmethylsulfonyl fluoride
    ODG
    n-octylglucoside
    TBST
    Tris-buffered saline/Tween 20
    HBSS+/+
    Hanks' balanced salt solution with Ca2+ and Mg2+
    ELISA
    enzyme-linked immunosorbent assay
    HEK
    human embryonic kidney
    GFP
    green fluorescent protein
    S
    scrambled.

  • Received June 3, 2011.
  • Accepted July 21, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (4)
Molecular Pharmacology
Vol. 80, Issue 4
1 Oct 2011
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Research ArticleArticle

Caveolin-1 and Cbp are Cooperative Csk Adaptors

Aaron T. Place, Zhenlong Chen, Farnaz R. Bakhshi, Guoquan Liu, John P. O'Bryan and Richard D. Minshall
Molecular Pharmacology October 1, 2011, 80 (4) 665-672; DOI: https://doi.org/10.1124/mol.111.073957

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Research ArticleArticle

Caveolin-1 and Cbp are Cooperative Csk Adaptors

Aaron T. Place, Zhenlong Chen, Farnaz R. Bakhshi, Guoquan Liu, John P. O'Bryan and Richard D. Minshall
Molecular Pharmacology October 1, 2011, 80 (4) 665-672; DOI: https://doi.org/10.1124/mol.111.073957
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