Chiariello, Mario and Visconti, Roberta and Carlomagno, Francesca and Melillo, Rosa Marina and Bucci, Cecilia and de Franciscis, Vittorio and Fox, Gary M. and Jing, Shuqian and Coso, Omar A. and Gutkind, J. Silvio and Fusco, Alfredo and Santoro, Massimo (1998) Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein Kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret. Oncogene, 16 (19). pp. 2435-2445. ISSN 0950-9232
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Abstract
The RET proto-oncogene encodes a functional receptor tyrosine kinase (Ret) for the Glial cell line Derived Neurotrophic Factor (GDNF). RET is involved in several neoplastic and non-neoplastic human diseases. Oncogenic activation of RET is detected in human papillary thyroid tumours and in multiple endocrine neoplasia type 2 syndromes. Inactivating mutations of RET have been associated to the congenital megacolon, i.e. Hirschprung's disease. In order to identify pathways that are relevant for Ret signalling to the nucleus, we have investigated its ability to induce the c-Jun NH2-terminal protein kinases (JNK). Here we show that triggering the endogenous Ret, expressed in PC12 cells, induces JNK activity; moreover, Ret is able to activate JNK either when transiently transfected in COS-1 cells or when stably expressed in NIH3T3 ®broblasts or in PC Cl 3 epithelial thyroid cells. JNK activation is dependent on the Ret kinase function, as a kinase-de®cient RET mutant, associated with Hirschsprung's disease, fails to activate JNK. The pathway leading to the activation of JNK by RET is clearly divergent from that leading to the activation of ERK: substitution of the tyrosine 1062 of Ret, the Shc binding site, for phenylalanine abrogates ERK but not JNK activation. Experiments conducted with dominant negative mutants or with negative regulators demonstrate that JNK activation by Ret is mediated by Rho/Rac related small GTPases and, particularly, by Cdc42.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Tyrosine kinase; transformation; jun; MEN2; thyroid |
| Subjects: | 500 Scienze naturali e Matematica 500 Scienze naturali e Matematica > 570 Scienze della vita; Biologia |
| Depositing User: | Dr Roberta Visconti |
| Date Deposited: | 11 Jan 2017 15:52 |
| Last Modified: | 11 Jan 2017 15:52 |
| URI: | http://eprints.bice.rm.cnr.it/id/eprint/15827 |
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