Allocca, Chiara (2016) Role of EPHA2 Serine 897 phosphorylation in thyroid cancer: molecular mechanisms and biological properties of a novel player in thyroid tumorigenesis. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Role of EPHA2 Serine 897 phosphorylation in thyroid cancer: molecular mechanisms and biological properties of a novel player in thyroid tumorigenesis
Creators:
CreatorsEmail
Allocca, Chiarachiaraallocca@libero.it
Date: 31 March 2016
Number of Pages: 110
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Scuola di dottorato: Medicina molecolare
Dottorato: Oncologia ed endocrinologia molecolare
Ciclo di dottorato: 28
Coordinatore del Corso di dottorato:
nomeemail
Santoro, Massimomasantor@unina.it
Tutor:
nomeemail
Santoro, MassimoUNSPECIFIED
Date: 31 March 2016
Number of Pages: 110
Uncontrolled Keywords: Thyroid cancer; EPH; EPHA2; p90RSK; pSer897 EPHA2; Ser897
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/04 - Patologia generale
Date Deposited: 11 Apr 2016 13:04
Last Modified: 17 Nov 2016 10:38
URI: http://www.fedoa.unina.it/id/eprint/11043

Abstract

EPH (Erythropoietin-Producing Hepatocellular carcinoma cell line) receptor tyrosine kinases (RTK) belong to the largest subfamily of RTKs counting 14 genes in humans. Among them, EPHA2 is often overexpressed in a variety of human cancers, including thyroid carcinoma. Thyroid carcinomas are commonly driven by genetic lesions targeting the MAPK signaling cascade including rearrangements of several RTKs, such as RET and NTRK, or point mutations in RAS or BRAF. We have previously demonstrated, through a siRNA-based genetic screen of the human kinome, that EPHA2 expression is essential for viability of thyroid cancer cells in culture. To gain insight into the EPHA2 function in thyroid tumorigenesis, we studied the role of the intracellular domain of EPHA2 and, in particular, of its phosphorylation on Serine 897 (pSer897). Ser897 phosphorylation has been previously reported to mediate EPHA2 oncogenic activity. Ser897 is embedded in the consensus phosphorylation sequence for AGC (PKA, PKG, PKC) family kinases, including p90RSK, a direct MAPK target. Here we show that in thyroid cancer cells bearing oncogenic lesions in the MAPK signaling cascade, EPHA2 is robustly phosphorylated on Ser897. Treatment with chemical inhibitors targeting p90RSK or other MAPK pathway components blunts Ser897 phosphorylation of EPHA2. Recombinant p90RSK phosphorylates in vitro EPHA2 Ser897. Finally, RNA interference-mediated knock-down combined with rescue experiments demonstrate that Ser897 phosphorylation of EPHA2 mediates thyroid cancer cell proliferation and motility. Collectively, these findings point to EPHA2 pSer897 as a novel crucial mediator of the oncogenic MAPK signaling cascade, and in particular of p90RSK, in thyroid cancer.

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