Time-resolved phosphoproteomics reveals scaffolding and catalysis-responsive patterns of SHP2-dependent signaling.

Autor:	Vemulapalli V; Department of Cancer Biology, Dana-Farber Cancer Institute Boston, Boston, United States.; Department of Biological Chemistry & Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, United States., Chylek LA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, United States., Erickson A; Department of Cell Biology, Harvard Medical School, Boston, United States., Pfeiffer A; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark., Gabriel KH; Department of Cancer Biology, Dana-Farber Cancer Institute Boston, Boston, United States.; Department of Biological Chemistry & Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, United States., LaRochelle J; Department of Cancer Biology, Dana-Farber Cancer Institute Boston, Boston, United States.; Department of Biological Chemistry & Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, United States., Subramanian K; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, United States., Cao R; Department of Cancer Biology, Dana-Farber Cancer Institute Boston, Boston, United States., Stegmaier K; Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, United States., Mohseni M; Novartis Institutes for Biomedical Research, Cambridge, United States., LaMarche MJ; Novartis Institutes for Biomedical Research, Cambridge, United States., Acker MG; Novartis Institutes for Biomedical Research, Cambridge, United States., Sorger PK; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, United States., Gygi SP; Department of Cell Biology, Harvard Medical School, Boston, United States., Blacklow SC; Department of Cancer Biology, Dana-Farber Cancer Institute Boston, Boston, United States.; Department of Biological Chemistry & Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Mar 23; Vol. 10. Date of Electronic Publication: 2021 Mar 23.
DOI:	10.7554/eLife.64251
Abstrakt:	SHP2 is a protein tyrosine phosphatase that normally potentiates intracellular signaling by growth factors, antigen receptors, and some cytokines, yet is frequently mutated in human cancer. Here, we examine the role of SHP2 in the responses of breast cancer cells to EGF by monitoring phosphoproteome dynamics when SHP2 is allosterically inhibited by SHP099. The dynamics of phosphotyrosine abundance at more than 400 tyrosine residues reveal six distinct response signatures following SHP099 treatment and washout. Remarkably, in addition to newly identified substrate sites on proteins such as occludin, ARHGAP35, and PLCγ2, another class of sites shows reduced phosphotyrosine abundance upon SHP2 inhibition. Sites of decreased phospho-abundance are enriched on proteins with two nearby phosphotyrosine residues, which can be directly protected from dephosphorylation by the paired SH2 domains of SHP2 itself. These findings highlight the distinct roles of the scaffolding and catalytic activities of SHP2 in effecting a transmembrane signaling response. Competing Interests: VV, LC, AE, AP, KG, JL, KS, RC, KS, PS, SG No competing interests declared, MM, ML, MA Novartis employee while this work was performed. SB SCB receives research funding for this project from Novartis, is a member of the SAB of Erasca, Inc, is an advisor to MPM Capital, and is a consultant on unrelated projects for IFM, Scorpion Therapeutics, and Ayala Therapeutics. (© 2021, Vemulapalli et al.)
Databáze:	MEDLINE
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