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EGF Regulates the Interaction of Tks4 with Src through Its SH2 and SH3 Domains

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    EGF Regulates the Interaction of Tks4 with Src through Its SH2 and SH3 Domains
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    • Metta Dülk
      Metta Dülk
      Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
      More by Metta Dülk
    • Bálint Szeder
      Bálint Szeder
      Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
      More by Bálint Szeder
    • Gábor Glatz
      Gábor Glatz
      Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, 1117 Budapest, Hungary
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    • Balázs L. Merő
      Balázs L. Merő
      Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
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    • Kitti Koprivanacz
      Kitti Koprivanacz
      Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
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    • Gyöngyi Kudlik
      Gyöngyi Kudlik
      Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
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    • Virág Vas
      Virág Vas
      Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
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    • Szabolcs Sipeki
      Szabolcs Sipeki
      Department of Medical Chemistry, Semmelweis University Medical School, 1094 Budapest, Hungary
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    • Anna Cserkaszky
      Anna Cserkaszky
      Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
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    • László Radnai*
      László Radnai
      Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
      *E-mail: [email protected]
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    • László Buday*
      László Buday
      Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
      Department of Medical Chemistry, Semmelweis University Medical School, 1094 Budapest, Hungary
      *E-mail: [email protected]
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      Orcidhttp://orcid.org/0000-0003-3518-5757
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    Biochemistry

    Cite this: Biochemistry 2018, 57, 28, 4186–4196
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.biochem.8b00084
    Published June 21, 2018
    Copyright © 2018 American Chemical Society
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    Abstract

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    The nonreceptor tyrosine kinase Src is a central component of the epidermal growth factor (EGF) signaling pathway. Our group recently showed that the Frank-ter Haar syndrome protein Tks4 (tyrosine kinase substrate with four Src homology 3 domains) is also involved in EGF signaling. Here we demonstrate that Tks4 and Src bind directly to each other and elucidate the details of the molecular mechanism of this complex formation. Results of GST pull-down and fluorescence polarization assays show that both a proline-rich SH3 binding motif (PSRPLPDAP, residues 466–474) and an adjacent phosphotyrosine-containing SH2 binding motif (pYEEI, residues 508–511) in Tks4 are responsible for Src binding. These motifs interact with the SH3 and SH2 domains of Src, respectively, leading to a synergistic enhancement of binding strength and a highly stable, “bidentate”-type of interaction. In agreement with these results, we found that the association of Src with Tks4 is permanent and the complex lasts at least 3 h in living cells. We conclude that the interaction of Tks4 with Src may result in the long term stabilization of the kinase in its active conformation, leading to prolonged Src activity following EGF stimulation.

    Copyright © 2018 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.biochem.8b00084.

    • Additional figures for sequence analysis of Tks4 and fluorescence polarization experiments (PDF)

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    Cited By

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    This article is cited by 20 publications.

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    Biochemistry

    Cite this: Biochemistry 2018, 57, 28, 4186–4196
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.biochem.8b00084
    Published June 21, 2018
    Copyright © 2018 American Chemical Society
    Request reuse permissions

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