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Regulation of heterotrimeric G protein βγ subunits mediated PI3K activation and leukocyte migration through a novel WD40‐WD40 repeat interaction between RACK1 and Gβγ
Author(s) -
Chen Songhai,
Lin Fang,
Shin MyungEun,
Wang Fei,
Hamm Heidi E.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a616-c
Subject(s) - heterotrimeric g protein , microbiology and biotechnology , chemotaxis , jurkat cells , pi3k/akt/mtor pathway , chemistry , g protein , signal transduction , biology , receptor , biochemistry , t cell , genetics , immune system
Many chemoattractants act through G protein‐mediated pathways to regulate leukocyte migration. Heterotrimeric G protein βγ subunits released from the activated Gi/o family of G proteins act as a molecular switch to trigger the activation of key signaling molecules such as PI3K to promote chemoattractant‐mediated directional cell migration. Here we describe the discovery of a novel mechanism of regulating leukocyte migration through the interaction of Gβγ with RACK1, receptor for activated C kinase 1, which is a novel binding partner of Gβγ that we previously identified and is a member of WD40 repeat proteins as is Gβ. We showed that RACK1 binds Gβγ through a novel WD40‐WD40 repeat interaction and its N‐terminal domain is the major determinant for binding Gβγ. Binding of full‐length RACK1 or its N‐terminal fragment to Gβγ inhibits Gβγ‐stimulated PI3Kγ activity in vitro due to the partial overlap of RACK1 and PI3Kγ binding sites on Gβγ as determined by using peptides derived from Gβ. Silencing RACK1 specifically enhances chemoattractant‐induced PI3K activation and concomitantly, chemotaxis of Jurkat and differentiated HL60 cells. Conversely, overexpression of RACK1 or its N‐terminal fragment reduces PI3K activity and cell motility. These findings indicate that RACK1 represents a novel regulatory protein involved in negatively modulating Gβγ‐mediated chemotaxis of leukocytes through PI3K.