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

• Autores: Lui, Vivian Wai Yan; Peyser, Noah D.; Ng, Patrick Kwok-Shing; Hritz, Jozef; Zeng, Yan; Lu, Yiling; Li, Hua; Wang, Lin; Gilbert, Breean R.; General, Ignacio; 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, Daniel E.; Grandis, Jennifer R.
• Año de publicación: 2014
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: DRIVER MUTATIONS; PHOSPHATASE MUTATIONS; STAT3 ACTIVATION
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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.
Fil: Lui, Vivian Wai Yan. University of Pittsburgh; Estados Unidos
Fil: Peyser, Noah D.. University of Pittsburgh; Estados Unidos
Fil: Ng, Patrick Kwok-Shing. University Of Texas Md Anderson Cancer Center;
Fil: Hritz, Jozef. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos. Masaryk University; República Checa
Fil: Zeng, Yan. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos
Fil: Lu, Yiling. University Of Texas Md Anderson Cancer Center;
Fil: Li, Hua. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos
Fil: Wang, Lin. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos
Fil: Gilbert, Breean R.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos
Fil: General, Ignacio. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos
Fil: Bahar, Ivet. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos
Fil: Ju, Zhenlin. University Of Texas Md Anderson Cancer Center;
Fil: Wang, Zhenghe. Case Western Reserve University; Estados Unidos
Fil: Pendleton, Kelsey P.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos
Fil: Xiao, Xiao. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos
Fil: Du, Yu. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos
Fil: Vries, John K.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos
Fil: Hammerman, Peter S.. Harvard Medical School; Estados Unidos
Fil: Garraway, Levi A.. Harvard Medical School; Estados Unidos
Fil: Mills, Gordon B.. University Of Texas Md Anderson Cancer Center;
Fil: Johnson, Daniel E.. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos
Fil: Grandis, Jennifer R.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos