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Concomitant activation of the PI3K-Akt and the Ras-ERK signaling pathways is essential for transformation by the V-SEA tyrosine kinase oncogene

Oncogene volume 21, pages 697–707 (2002)Cite this article

Abstract

V-SEA is the transforming component of S13 Avian Erythroblastosis Retrovirus that causes erythroblastosis and anemia in chicken. Like all members in the family (MET, RON, SEA), its cytosolic domain possesses two tyrosine autophosphorylation sites in the tandemly arranged bidentate motif that serve as docking sites for SH2 domain-containing proteins. Here, we investigated phosphotyrosine-dependent activation of signaling pathways and their significance in V-SEA-induced transformation and/or proliferation. We demonstrated that V-SEA activates the PI3K-Akt signaling pathway primarily in Y557- and secondarily in Y564-dependent manner. V-SEA was also shown to induce the tyrosine phosphorylation of the Gab2 protein, leading to PI3K association and thus providing an alternative route for PI3K activation. On the other hand, activation of the Ras-ERK pathway is primarily via Y564 and secondarily via Y557. A dominant-negative form of Ras inhibited V-SEA-induced ERK phosphorylation in concentration dependent manner suggesting the importance of the Grb2-Ras signaling axis in V-SEA-induced ERK activation. The biological significance of activation of the PI3K-Akt and the Ras-ERK pathways in V-SEA-induced transformation was analysed in the V-SEA-RAT1 and V-SEA-3T3 cell lines by employing specific inhibitors, LY294002 and PD98059 compounds. Both the PD and LY compounds inhibited cell growth, but only the PD compound caused reversion of the transformed phenotype. In addition, both compounds inhibited focal colony formation by the transformants in soft agar. Thus, transformation by the V-SEA oncogene is a function of the concomitant activation of, at least, the PI3K-Akt and Ras-ERK signaling pathways that regulate cell growth and morphology.

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  1. Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, New York, 11794-5222, NY, USA

    Yehenew Agazie, Irene Ischenko & Michael Hayman

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  1. Yehenew Agazie
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  2. Irene Ischenko
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Correspondence to Michael Hayman.

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Agazie, Y., Ischenko, I. & Hayman, M. Concomitant activation of the PI3K-Akt and the Ras-ERK signaling pathways is essential for transformation by the V-SEA tyrosine kinase oncogene. Oncogene 21, 697–707 (2002). https://doi.org/10.1038/sj.onc.1205115

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