1 research outputs found
Structural and Functional Consequences of Three Cancer-Associated Mutations of the Oncogenic Phosphatase SHP2
The proto-oncogene <i>PTPN11</i> 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 <i>PTPN11</i> 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