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

Vivian Wai Yan Lui, Noah D. Peyser, Patrick Kwok Shing Ng, Jozef Hritz, Yan Zeng, Yiling Lu, Hua Li, Lin Wang, Breean R. Gilbert, Ignacio J. General, Ivet Bahar, Zhenlin Ju, Zhenghe Wang, Kelsey P. Pendleton, Xiao Xiao, Yu Du, John K. Vries, Peter S. Hammerman, Levi A. Garraway, Gordon B. MillsDaniel E. Johnson, Jennifer R. Grandis

    Research output: Contribution to journalArticle

    49 Scopus citations

    Abstract

    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-tyrosinesubstrate 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.

    Original languageEnglish (US)
    Pages (from-to)1114-1119
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume111
    Issue number3
    DOIs
    StatePublished - Jan 21 2014

    Keywords

    • Driver mutations
    • Phosphatase mutations
    • Stat3 activation

    ASJC Scopus subject areas

    • General

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  • Cite this

    Lui, V. W. Y., Peyser, N. D., Ng, P. K. S., Hritz, J., Zeng, Y., Lu, Y., Li, H., Wang, L., Gilbert, B. R., General, I. J., Bahar, I., Ju, Z., Wang, Z., Pendleton, K. P., Xiao, X., Du, Y., Vries, J. K., Hammerman, P. S., Garraway, L. A., ... Grandis, J. R. (2014). 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 of the United States of America, 111(3), 1114-1119. https://doi.org/10.1073/pnas.1319551111