Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer
Proceedings of the National Academy of Sciences, 2014•National Acad Sciences
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 …
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 …
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.
National Acad Sciences