GAB2 is involved in differential pi3-kinase signaling by two splice forms of C-kit.

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Abstract

The stem cell factor receptor/c-Kit plays an important physiological role in hematopoesis, melanogenesis and gametogenesis. It has also been implicated in numerous human malignancies. Signal transduction pathways shown to be of importance for c-Kit mediated transformation include the PI3-kinase/Akt pathway. We have previously shown that two alternative splice forms of c-Kit, denoted GNNK- and GNNK+ respectively, mediate distinctively different signals. In this study we find that in the hematopoietic cell line Ba/F3, the GNNK- c-Kit mediates a substantially stronger activation of PI3-kinase/Akt than the GNNK+ c-Kit. This difference in signaling was shown to be dependent on the association of the scaffolding protein Gab2 to c-Kit and Src-mediated phosphorylation of Gab2, to be independent of the direct association of PI3-kinase with c-Kit. Furthermore, proliferation and survival of Ba/F3 cells expressing a mutant of c-Kit that fails to bind to PI3-kinase directly was slightly decreased compared to wild-type c-Kit expressing cells. Using siRNA technology we further verified a role of Gab2 in inducing activation of PI3-kinase/Akt downstream of c-Kit. To summarize, we show that PI3-kinase activation by c-Kit is both splice form dependent and cell type specific. Furthermore, activation of PI3-kinase by c-Kit is dependent both on the direct PI3-kinase binding site in c-Kit as well as on the phosphorylation of Gab2. The fact that c-Kit has been found mutated in numerous human malignancies including acute myeloid leukemia and that Gab2 often is overexpressed in acute myeloid leukemia suggests a potential role of Gab2 mediated PI3-kinase activation in transformation.

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  • Medicinal Chemistry
Original languageEnglish
Pages (from-to)27444-27451
JournalJournal of Biological Chemistry
Volume283
Issue number41
Publication statusPublished - 2008
Publication categoryResearch
Peer-reviewedYes

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The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)

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