Time resolved quantitative phosphoproteomics reveals distinct patterns of SHP2 dependence in EGFR signaling
Time resolved quantitative phosphoproteomics reveals distinct patterns of SHP2 dependence in EGFR signaling
Abstract SHP2 is a protein tyrosine phosphatase that normally potentiates intracellular signaling by growth factors, antigen receptors, and some cytokines; it is frequently mutated in childhood leukemias and other cancers. 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 the small molecule SHP099. Data on phosphotyrosine abundance at more than 400 tyrosine residues reveals six distinct response signatures following SHP099 treatment and washout. These include putative substrate sites with increased phosphotyrosine abundance at early or late timepoints, and another class of sites that shows reduced phosphotyrosine abundance when SHP099 is present. 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 how analysis of phosphoproteomic dynamics can provide insight into transmembrane signaling responses.
LaMarche Matthew、Mohseni Morvarid、Chylek Lily、LaRochelle Jonathan、Acker Michael G.、Blacklow Stephen C.、Sorger Peter K.、Gygi Steven P.、Vemulapalli Vidyasiri、Erickson Alison、Subramanian Kartik
Novartis Institutes for Biomedical Research, CambridgeNovartis Institutes for Biomedical Research, CambridgeLaboratory of Systems Pharmacology, Harvard Medical SchoolDepartment of Cancer Biology, Dana-Farber Cancer Institute Boston||Department of Biological Chemistry & Molecular Pharmacology, Blavatnik Institute, Harvard Medical SchoolNovartis Institutes for Biomedical Research, CambridgeDepartment of Cancer Biology, Dana-Farber Cancer Institute Boston||Department of Biological Chemistry & Molecular Pharmacology, Blavatnik Institute, Harvard Medical SchoolLaboratory of Systems Pharmacology, Harvard Medical SchoolDepartment of Cell Biology, Harvard Medical SchoolDepartment of Cancer Biology, Dana-Farber Cancer Institute Boston||Department of Biological Chemistry & Molecular Pharmacology, Blavatnik Institute, Harvard Medical SchoolDepartment of Cell Biology, Harvard Medical SchoolLaboratory of Systems Pharmacology, Harvard Medical School
医学研究方法基础医学分子生物学
LaMarche Matthew,Mohseni Morvarid,Chylek Lily,LaRochelle Jonathan,Acker Michael G.,Blacklow Stephen C.,Sorger Peter K.,Gygi Steven P.,Vemulapalli Vidyasiri,Erickson Alison,Subramanian Kartik.Time resolved quantitative phosphoproteomics reveals distinct patterns of SHP2 dependence in EGFR signaling[EB/OL].(2025-03-28)[2025-05-24].https://www.biorxiv.org/content/10.1101/598664.点此复制
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