Publication details

Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer


LUI Vivian Way Y. PEYSER Noah D. NG Patrick KS HRITZ Jozef ZENG Yan LU Yiling LI Hua WANG Lins GILBERT Breean R. GENERAL Ignacio J. BAHAR Ivet JU Zhenlin WANG Zhenghe PENDLETON Kelsey P. XIAO Xiao DU Yu VRIES John K. HAMMERMAN Peter S. GARRAWAY Levi A. MILLS Gordon B. JOHNSON Dean Kim GRANDIS Jennifer R.

Year of publication 2014
Type Article in Periodical
Magazine / Source Proceedings of the National Academy of Sciences of the United States of America
MU Faculty or unit

Central European Institute of Technology

Field Other medical specializations
Keywords STAT3 activation; driver mutations; phosphatase mutations
Description 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.

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