title: Structural and Functional Consequences of Three Cancer-Associated Mutations of the Oncogenic Phosphatase SHP2.
abstract: The proto-oncogene PTPN11 encodes a cytoplasmic protein tyrosine phosphatase, SHP2, which is required for normal development and sustained activation of the Ras-MAPK signaling pathway. Germline mutations in SHP2 cause developmental disorders, and somatic mutations have been identified in childhood and adult cancers and drive leukemia in mice. Despite our knowledge of the PTPN11 variations associated with pathology, the structural and functional consequences of many disease-associated mutants remain poorly understood. Here, we combine X-ray crystallography, small-angle X-ray scattering, and biochemistry to elucidate structural and mechanistic features of three cancer-associated SHP2 variants harboring single point mutations within the N-SH2:PTP interdomain autoinhibitory interface. Our findings directly compare the impact of each mutation on autoinhibition of the phosphatase and advance the development of structure-guided and mutation-specific SHP2 therapies.
authors.affiliation: Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.|Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: LaRochelle
authors.forename: Michelle
authors.initials: M
authors.lastname: Fodor
authors.affiliation: Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.|Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.|Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Izabela
authors.initials: I
authors.lastname: Durzynska
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.
authors.forename: Lixin
authors.initials: L
authors.lastname: Fan
authors.forename: Travis
authors.initials: T
authors.lastname: Stams
authors.forename: Ho Man
authors.initials: HM
authors.lastname: Chan
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: LaMarche
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Pascal D
authors.initials: PD
authors.lastname: Fortin
authors.forename: Michael G
authors.initials: MG
authors.lastname: Acker
authors.affiliation: Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.|Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Blacklow
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000235:genetics; D008024:Ligands; D008958:Models, Molecular; D009369:Neoplasms / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics; D017354:Point Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D053838:Scattering, Small Angle; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11