Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer.
Lui, VW; Peyser, ND; Ng, PK; Hritz, J; Zeng, Y; Lu, Y; Li, H; Wang, L; Gilbert, BR; General, IJ; Bahar, I; Ju, Z; Wang, Z; Pendleton, KP; Xiao, X; Du, Y; Vries, JK; Hammerman, PS; Garraway, LA; Mills, GB; Johnson, DE; Grandis, JR
Proceedings of the National Academy of Sciences of the United States of America
111
1114-9
2014
Mostrar resumen
The underpinnings of STAT3 hyperphosphorylation resulting in enhanced signaling and cancer progression are incompletely understood. Loss-of-function mutations of enzymes that dephosphorylate STAT3, such as receptor protein tyrosine phosphatases, which are encoded by the PTPR gene family, represent a plausible mechanism of STAT3 hyperactivation. We analyzed whole exome sequencing (n = 374) and reverse-phase protein array data (n = 212) from head and neck squamous cell carcinomas (HNSCCs). PTPR mutations are most common and are associated with significantly increased phospho-STAT3 expression in HNSCC tumors. Expression of receptor-like protein tyrosine phosphatase T (PTPRT) mutant proteins induces STAT3 phosphorylation and cell survival, consistent with a "driver" phenotype. Computational modeling reveals functional consequences of PTPRT mutations on phospho-tyrosine-substrate interactions. A high mutation rate (30%) of PTPRs was found in HNSCC and 14 other solid tumors, suggesting that PTPR alterations, in particular PTPRT mutations, may define a subset of patients where STAT3 pathway inhibitors hold particular promise as effective therapeutic agents. | 24395800
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