Phosphoinositide 3-kinase-dependent regulation of interleukin-3-induced proliferation: involvement of mitogen-activated protein kinases, SHP2 and Gab2

The Journal of Biological Chemistry
B L CraddockMelanie J Welham

Abstract

We have demonstrated previously that class I(A) phosphoinositide 3-kinases play a major role in regulation of interleukin-3 (IL)-3-dependent proliferation. Investigations into the downstream targets involved have identified the MAPK cascade as a target. Expression of Deltap85 and incubation with LY294002 both inhibited IL-3-induced activation of Mek, Erk1, and Erk2. This was most pronounced during the initial phase of Erk activation. The Mek inhibitor, PD98059, blocked IL-3-driven proliferation, an effect enhanced by Deltap85 expression, suggesting that inhibition of Mek and Erks by Deltap85 contributes to the decrease in IL-3-induced proliferation in these cells but that additional pathways may also be involved. To investigate the mechanism leading to decreased activation of Erks, we investigated effects on SHP2 and Gab2, both implicated in IL-3 regulation of Erk activation. Expression of Deltap85 led to a reduction in SHP2 tyrosine phosphorylation and its ability to interact with Grb2 and Gab2 but increased overall tyrosine phosphorylation of Gab2. LY294002 did not perturb SHP2 interactions, potentially related to differences in the effects of these inhibitors on levels of phosphoinositides. These results imply that the regul...Continue Reading

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Citations

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May 15, 2002·Immunology Letters·Gábor KonczGabriella Sármay
Jun 19, 2002·The Journal of Experimental Medicine·Laura VelazquezTony Pawson
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Jun 27, 2006·Bioorganic & Medicinal Chemistry·Enrique RocheBernat Soria
Jul 25, 2003·The Journal of Biological Chemistry·Hicham LahlouChristiane Susini
Nov 12, 2005·The Journal of Biological Chemistry·Xiao-Jun QiPhilip H Howe
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Feb 21, 2003·The Journal of Biological Chemistry·Liangping YuanCheng-Kui Qu
Jun 11, 2002·American Journal of Physiology. Cell Physiology·Tim R BilderbackKarin D Rodland
May 2, 2003·The Journal of Biological Chemistry·Mairi MacGillivrayGregory P Downey
Oct 17, 2015·Molecular and Cellular Biochemistry·Francisco J Rodríguez-ÁlvarezMa José Toro
Jan 6, 2007·The Journal of Biological Chemistry·Mike P StormMelanie J Welham
Aug 26, 2004·The Journal of Biological Chemistry·Nicholas R D PalingMelanie J Welham

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