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-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.STAT3 activation | driver mutations | phosphatase mutations T yrosine phosphorylation regulates a multitude of cellular processes by coordinately activating and inactivating signaling proteins. Aberrations of protein tyrosine phosphorylation and signaling are a hallmark for oncogenic events found in most human cancers. The phosphorylation/dephosphorylation of tyrosine residues on signaling proteins is directly mediated by protein tyrosine kinases and phosphatases. Although many cellular factors are known to dynamically control the activity of these enzymes, genetic alterations of kinases and phosphatases in human cancers lead to perturbations in the levels of tyrosine phosphorylated proteins, uncontrolled cell growth, and tumor formation. Although activating mutations of tyrosine kinases have been extensively studied (1, 2), cancer-associated mutations of tyrosine phosphatases remain incompletely understood, partly due to the lack of comprehensive genomic analysis of these large arrays of phosphatases, as well as their largely unknown and often ambiguous actions in normal physiology and cancer biology.Among the 107 known protein tyrosine phosphatases, the receptor protein tyrosine phosphatases (RPTPs) represent the largest family of the human tyrosine phosphatome, comprising 21 family members (3). These RPTPs are believed to be crucial for the regulation of inter-as well as intracellular signaling due to the cell-surface localization of RPTPs. Selected members of the RPTP family have been reported to function as tumor suppressors, where gene mutation, deletion, or methylation may contribute to the cancer phenotype (3).STAT3 is an oncogene, and constitutive STAT3 activation is a hallmark of human cancers. Activating STAT3 mutations are rare in all cancers studied to date, including head and neck squamous cell carcinoma (HNSCC) (4). Although activating mutations of upst...

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

“…Noteworthy among novel hits were several single pass type one plasma membrane proteins, which are members of the protein tyrosine phosphatase family: PTPRS (reduced 6.3-fold), PTPRF (reduced 5.3-fold), PTPRG (reduced 4.1-fold), and PTPRU (reduced 2.9-fold). PTPR family members have been implicated as important tumor suppressors (29). In support of this, PTPRS levels were rescued in MEDI3622-treated tumors in a dose-dependent manner (Figs.…”

“…PTPRS was a noteworthy hit for four reasons. First, PTPR proteins are mutated with a 30% frequency across 15 types of solid tumors (29). Second, PTPRS is specifically microdeleted in 26% of head and neck cancer patients (34).…”

JNK1/2 expression and modulation of STAT3 signaling in oral cancer

“…However, the role of serine phosphorylation is less well understood. Although there is significant evidence in favor of the important role of STAT3 in head and neck cancer, the mechanism of STAT3 hyperactivation in this type of cancer remains to be completely understood (59). STAT proteins are important downstream targets of MAPKs, which are involved in the regulation of STAT proteins through crosstalk signaling (12).…”

Identification of Subsets of Genetic Alterations in KRAS-mutant Lung Cancer using Association Rule Mining

“…The role of PTPRs in lung 17, 2017; cancer is yet to be unraveled. However, phospho-STAT3 is a substrate for these phosphatases [40,41] and frequent loss of function mutations in PTPRT and PTPRD have been linked to hyperphosphorylation of STAT3 in head and neck squamous carcinoma and in gliomagenesis [42][43][44]. STAT3 is hyperactive in some lung cancers [45].…”

“…Mutations in PTPRs can lead to constitutive activation of STAT3 which is associated with many lung cancer [42][43][44]. PTPRs alterations were collectively altered in at least 50% of KRASmutant tumors (Table 1).…”