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Vol. 19, Issue 9, 3909-3922, September 2008

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RACK1 Regulates Directional Cell Migration by Acting on Gβ at the Interface with Its Effectors PLCβ and PI3K

Songhai Chen^*,, Fang Lin^*, Myung Eun Shin, Fei Wang, Lixin Shen^*, and Heidi E. Hamm^*

*Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; and Department of Cell and Developmental Biology, University of Illinois, Urbana, IL 61801

Submitted April 28, 2008; Revised June 18, 2008; Accepted June 20, 2008
Monitoring Editor: Sandra L. Schmid

Migration of cells up the chemoattractant gradients is mediated by the binding of chemoattractants to G protein–coupled receptors and activation of a network of coordinated excitatory and inhibitory signals. Although the excitatory process has been well studied, the molecular nature of the inhibitory signals remains largely elusive. Here we report that the receptor for activated C kinase 1 (RACK1), a novel binding protein of heterotrimeric G protein β (Gβ) subunits, acts as a negative regulator of directed cell migration. After chemoattractant-induced polarization of Jurkat and neutrophil-like differentiated HL60 (dHL60) cells, RACK1 interacts with Gβ and is recruited to the leading edge. Down-regulation of RACK1 dramatically enhances chemotaxis of cells, whereas overexpression of RACK1 or a fragment of RACK1 that retains Gβ-binding capacity inhibits cell migration. Further studies reveal that RACK1 does not modulate cell migration through binding to other known interacting proteins such as PKCβ and Src. Rather, RACK1 selectively inhibits Gβ-stimulated phosphatidylinositol 3-kinase (PI3K) and phospholipase C (PLC) β activity, due to the competitive binding of RACK1, PI3K, and PLCβ to Gβ. Taken together, these findings provide a novel mechanism of regulating cell migration, i.e., RACK1-mediated interference with Gβ-dependent activation of key effectors critical for chemotaxis.

Present address: Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.

Address correspondence to: Songhai Chen (songhai.chen{at}Vanderbilt.edu) or Heidi E. Hamm (heidi.hamm{at}Vanderbilt.edu)

Abbreviations used: dHL60, differentiated HL60; ERK, extracellular signal-regulated kinase; fMLP, f-Met-Leu-Phe; GPCR, G protein–coupled receptor; Gβ, G protein β; GRK2-ct, the C-terminal tail of G protein–coupled receptor kinase 2; IP, inositol phosphate; PH, pleckstrin homology; PI3K, phosphatidylinositol 3-kinase; PIP₃, phosphatidylinositol 3,4,5-trisphosphate; PKC, protein kinase C; PLC, phospholipase C; PTx, pertussis toxin; RACK1, receptor for activated C kinase 1.

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