title: Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer.
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-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.
authors.affiliation: Departments of Otolaryngology, Pharmacology and Chemical Biology, Structural Biology, and Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Vivian Wai Yan
authors.initials: VW
authors.lastname: Lui
authors.forename: Noah D
authors.initials: ND
authors.lastname: Peyser
authors.forename: Patrick Kwok-Shing
authors.initials: PK
authors.lastname: Ng
authors.forename: Jozef
authors.initials: J
authors.lastname: Hritz
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Breean R
authors.initials: BR
authors.lastname: Gilbert
authors.forename: Ignacio J
authors.initials: IJ
authors.lastname: General
authors.forename: Ivet
authors.initials: I
authors.lastname: Bahar
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Ju
authors.forename: Zhenghe
authors.initials: Z
authors.lastname: Wang
authors.forename: Kelsey P
authors.initials: KP
authors.lastname: Pendleton
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.forename: Yu
authors.initials: Y
authors.lastname: Du
authors.forename: John K
authors.initials: JK
authors.lastname: Vries
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Johnson
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival; D003198:Computer Simulation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D020543:Proteome; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014162:Transfection
chemical_list: D020543:Proteome; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C516865:PTPRT protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
keywords: STAT3 activation; driver mutations; phosphatase mutations