Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4,5-biphosphate hydrolysis

Oncogene
Toranoshin AyadaAkihiko Yoshimura

Abstract

Sproutys have been shown to negatively regulate growth factor-induced extracellular signal-regulated kinase (ERK) activation, and suggested to be an anti-oncogene. However, molecular mechanism of the suppression has not yet been clarified completely. Sprouty4 inhibits vascular endothelial growth factor (VEGF)-A-induced ERK activation, but not VEGF-C-induced ERK activation. It has been shown that VEGF-A-mediated ERK activation is strongly dependent on protein kinase C (PKC), whereas that by VEGF-C is dependent on Ras. This suggests that Sprouty4 inhibits the PKC pathway more specifically than the Ras pathway. In this study, we confirmed that Sprouty4 suppressed various signals downstream of PKC, such as phosphorylation of MARCKS and protein kinase D (PKD), as well as PKC-dependent nuclear factor (NF)-kappaB activation. Furthermore, Sprouty4 suppressed upstream signals of PKC, such as Ca(2+) mobilization, phosphatidylinositol 4,5-biphosphate (PIP(2)) breakdown and inositol 1,4,5-triphosphate (IP(3)) production in response to VEGF-A. Those effects were dependent on the C-terminal cysteine-rich region, but not on the N-terminal region of Sprouty4, which is critical for the suppression of fibroblast growth factor (FGF)-mediated ERK ...Continue Reading

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Citations

Oct 19, 2011·The Journal of Biological Chemistry·Kimberly AndersonTarun B Patel
Aug 20, 2010·Molecular Biology of the Cell·Simge AkbulutJonathan D Licht
Oct 28, 2010·Development·Karel Dorey, Enrique Amaya
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Apr 16, 2014·Biochemical and Biophysical Research Communications·Tomohiro FukayaAkihiko Yoshimura
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Aug 17, 2019·International Journal of Molecular Sciences·Francesco MocciaGermano Guerra
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Jun 15, 2021·Proceedings of the Japan Academy. Series B, Physical and Biological Sciences·Akihiko YoshimuraMinako Ito

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