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 (original) (raw)

Oncogene volume 16, pages 2435–2445 (1998)Cite this article

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 fibroblasts or in PC Cl 3 epithelial thyroid cells. JNK activation is dependent on the Ret kinase function, as a kinase-deficient 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.

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Author notes

  1. Mario Chiariello and Roberta Visconti: M Chiariello and R Visconti contributed equally to this work

Authors and Affiliations

  1. c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Facoltà di Medicina e Chirurgia, Università di Napoli `Federico II', via S Pansini 5, Naples, 80131, Italy
    Mario Chiariello, Roberta Visconti, Francesca Carlomagno, Rosa Marina Melillo, Cecilia Bucci, Vittorio de Franciscis & Massimo Santoro
  2. Amgen, 1840 DeHavilland Drive, Thousand Oaks, 91320-1789, California, USA
    Gary M Fox & Shuqian Jing
  3. Oral and Pharyngeal Cancer Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Omar A Coso & J Silvio Gutkind
  4. Dipartimento di Medicina Sperimentale e Clinica, Facoltà di Medicina e Chirurgia di Catanzaro, Università di Reggio Calabria, via T Campanella 5, Catanzaro, 88100, Italy
    Alfredo Fusco

Authors

  1. Mario Chiariello
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  2. Roberta Visconti
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  3. Francesca Carlomagno
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  4. Rosa Marina Melillo
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  5. Cecilia Bucci
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  6. Vittorio de Franciscis
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  7. Gary M Fox
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  8. Shuqian Jing
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  9. Omar A Coso
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  10. J Silvio Gutkind
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  11. Alfredo Fusco
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  12. Massimo Santoro
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Chiariello, M., Visconti, R., Carlomagno, F. et al. 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, 2435–2445 (1998). https://doi.org/10.1038/sj.onc.1201778

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