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Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition

Author

Listed:
  • Jonathan R. LaRochelle

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Michelle Fodor

    (Novartis Institutes for Biomedical Research)

  • Vidyasiri Vemulapalli

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Morvarid Mohseni

    (Novartis Institutes for Biomedical Research)

  • Ping Wang

    (Novartis Institutes for Biomedical Research)

  • Travis Stams

    (Novartis Institutes for Biomedical Research)

  • Matthew J. LaMarche

    (Novartis Institutes for Biomedical Research)

  • Rajiv Chopra

    (Novartis Institutes for Biomedical Research)

  • Michael G. Acker

    (Novartis Institutes for Biomedical Research)

  • Stephen C. Blacklow

    (Harvard Medical School
    Dana-Farber Cancer Institute)

Abstract

Activating mutations in PTPN11, encoding the cytosolic protein tyrosine phosphatase SHP2, result in developmental disorders and act as oncogenic drivers in patients with hematologic cancers. The allosteric inhibitor SHP099 stabilizes the wild-type SHP2 enzyme in an autoinhibited conformation that is itself destabilized by oncogenic mutations. Here, we report the impact of the highly activated and most frequently observed mutation, E76K, on the structure of SHP2, and investigate the effect of E76K and other oncogenic mutations on allosteric inhibition by SHP099. SHP2E76K adopts an open conformation but can be restored to the closed, autoinhibited conformation, near-identical to the unoccupied wild-type enzyme, when complexed with SHP099. SHP099 inhibitory activity against oncogenic SHP2 variants in vitro and in cells scales inversely with the activating strength of the mutation, indicating that either oncoselective or vastly more potent inhibitors will be necessary to suppress oncogenic signaling by the most strongly activating SHP2 mutations in cancer.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06823-9
    DOI: 10.1038/s41467-018-06823-9
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    Cited by:

    1. 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.

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