期刊
CELL ADHESION & MIGRATION
卷 5, 期 3, 页码 237-248出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cam.5.3.15909
关键词
G proteins; girdin; guanine nucleotide exchange factor; epidermal growth factor-receptor; G protein coupled receptors; metastasis; migration-proliferation dichotomy; growth factors; alternative splicing; PI3-kinase; Akt; rheostat; actin cytoskeleton
类别
资金
- Burroughs Wellcome Fund
- Doris Duke Charitable Foundation
- American Gastroenterology Associate
- NIH [CA100768, DKI7780]
- Susan G. Komen Postdoctoral fellowship [KG080079]
GIV/Girdin is a multidomain signaling molecule that enhances PI3K-Akt signals downstream of both G protein-coupled and growth factor receptors. We previously reported that GIV triggers cell migration via its C-terminal guanine nucleotide exchange factor (GEF) motif that activates G alpha i. Recently we discovered that GIV's C-terminus directly interacts with the epidermal growth factor receptor (EGFR) and when its GEF function is intact, a G alpha i-GIV-EGFR signaling complex assembles. By coupling G proteins to growth factor receptors, GIV is uniquely poised to intercept the incoming receptor-initiated signals and modulate them via G protein intermediates. Subsequent work has revealed that expression of the highly specialized C-terminus of GIV undergoes a bipartite dysregulation during oncogenesis- full-length GIV with an intact C-terminus is expressed at levels similar to 20-50-fold above normal in highly invasive cancer cells and metastatic tumors, but its C-terminus is truncated by alternative splicing in poorly invasive cancer cells and non-invasive tumors. The consequences of such dysregulation on graded signal transduction and cellular phenotypes in the normal epithelium and its implication during tumor progression are discussed herein. Based on the fact that GIV grades incoming signals initiated by ligand-activated receptors by linking them to cyclical activation of G proteins, we propose that GIV is a molecular rheostat for signal transduction.
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