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Structural insights into the pSer/pThr dependent regulation of the SHP2 tyrosine phosphatase in insulin and CD28 signaling

Author

Listed:
  • András Zeke

    (Institute of Enzymology, Research Centre for Natural Sciences
    Institute of Organic Chemistry, Research Centre for Natural Sciences)

  • Tamás Takács

    (Insitute of Enzymology, Research Centre for Natural Sciences
    ELTE Eötvös Loránd University)

  • Péter Sok

    (Institute of Organic Chemistry, Research Centre for Natural Sciences)

  • Krisztina Németh

    (Institute of Organic Chemistry, Research Centre for Natural Sciences)

  • Klára Kirsch

    (Institute of Organic Chemistry, Research Centre for Natural Sciences)

  • Péter Egri

    (Institute of Organic Chemistry, Research Centre for Natural Sciences)

  • Ádám Levente Póti

    (Institute of Organic Chemistry, Research Centre for Natural Sciences)

  • Isabel Bento

    (EMBL Outstation Hamburg)

  • Gábor E. Tusnády

    (Institute of Enzymology, Research Centre for Natural Sciences)

  • Attila Reményi

    (Institute of Organic Chemistry, Research Centre for Natural Sciences)

Abstract

Serine/threonine phosphorylation of insulin receptor substrate (IRS) proteins is well known to modulate insulin signaling. However, the molecular details of this process have mostly been elusive. While exploring the role of phosphoserines, we have detected a direct link between Tyr-flanking Ser/Thr phosphorylation sites and regulation of specific phosphotyrosine phosphatases. Here we present a concise structural study on how the activity of SHP2 phosphatase is controlled by an asymmetric, dual phosphorylation of its substrates. The structure of SHP2 has been determined with three different substrate peptides, unveiling the versatile and highly dynamic nature of substrate recruitment. What is more, the relatively stable pre-catalytic state of SHP2 could potentially be useful for inhibitor design. Our findings not only show an unusual dependence of SHP2 catalytic activity on Ser/Thr phosphorylation sites in IRS1 and CD28, but also suggest a negative regulatory mechanism that may also apply to other tyrosine kinase pathways as well.

Suggested Citation

  • András Zeke & Tamás Takács & Péter Sok & Krisztina Németh & Klára Kirsch & Péter Egri & Ádám Levente Póti & Isabel Bento & Gábor E. Tusnády & Attila Reményi, 2022. "Structural insights into the pSer/pThr dependent regulation of the SHP2 tyrosine phosphatase in insulin and CD28 signaling," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32918-5
    DOI: 10.1038/s41467-022-32918-5
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    References listed on IDEAS

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    1. Eunhee Choi & Sotaro Kikuchi & Haishan Gao & Karolina Brodzik & Ibrahim Nassour & Adam Yopp & Amit G. Singal & Hao Zhu & Hongtao Yu, 2019. "Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    2. Gerjon J. Ikink & Mandy Boer & Elvira R. M. Bakker & John Hilkens, 2016. "IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation," Nature Communications, Nature, vol. 7(1), pages 1-15, December.
    3. Jonathan R. LaRochelle & Michelle Fodor & Vidyasiri Vemulapalli & Morvarid Mohseni & Ping Wang & Travis Stams & Matthew J. LaMarche & Rajiv Chopra & Michael G. Acker & Stephen C. Blacklow, 2018. "Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    4. Yoshihito Kano & Teklab Gebregiworgis & Christopher B. Marshall & Nikolina Radulovich & Betty P. K. Poon & Jonathan St-Germain & Jonathan D. Cook & Ivette Valencia-Sama & Benjamin M. M. Grant & Silvia, 2019. "Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
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