RACK1 Regulates Directional Cell Migration by Acting on Gβγ at the Interface with Its Effectors PLCβ and PI3Kγ

Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
Molecular biology of the cell (Impact Factor: 4.47). 08/2008; 19(9):3909-22. DOI: 10.1091/mbc.E08-04-0433
Source: PubMed


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 betagamma (G betagamma) 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 G betagamma 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 G betagamma-binding capacity inhibits cell migration. Further studies reveal that RACK1 does not modulate cell migration through binding to other known interacting proteins such as PKC beta and Src. Rather, RACK1 selectively inhibits G betagamma-stimulated phosphatidylinositol 3-kinase gamma (PI3K gamma) and phospholipase C (PLC) beta activity, due to the competitive binding of RACK1, PI3K gamma, and PLC beta to G betagamma. Taken together, these findings provide a novel mechanism of regulating cell migration, i.e., RACK1-mediated interference with G betagamma-dependent activation of key effectors critical for chemotaxis.

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    • "Signaling molecules downstream of chemokine receptors can also modulate chemotaxis. Receptor for activated C kinase 1 (RACK1) serves as a negative regulator for leukocyte chemotaxis through competitive binding to G βγ and blockade of its binding interface for the downstream effectors, phosphatidylinositol 3-kinase γ (PI3Kγ) and phospholipase C β (PLCβ), involved in directional migration [113]. "
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    • "The involvement of mammalian RACK1 in these vesicular traffic and endosome recycling processes could occur at the level of interaction with one of its binding partners, PI3K. For example , it has been reported that PI3K has a fundamental role in Rab11 localization during mitosis in Caenorhabditis elegans (Ai et al. 2009; Chen et al. 2008; McCahill et al. 2002). Alternatively , based on the deteriorated appearance of the knockdown nodules, an additional effect of PvRACK1 silencing could be the induction of early senescence of the nodule. "
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