Journal article
RACK1 Regulates Directional Cell Migration by Acting on Gβγ at the Interface with Its Effectors PLCβ and PI3Kγ
Molecular biology of the cell, Vol.19(9), pp.3909-3922
09/2008
DOI: 10.1091/mbc.e08-04-0433
PMCID: PMC2526680
PMID: 18596232
Abstract
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 βγ (Gβγ) 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 Gβγ 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 Gβγ-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 Gβγ-stimulated phosphatidylinositol 3-kinase γ (PI3Kγ) and phospholipase C (PLC) β activity, due to the competitive binding of RACK1, PI3Kγ, and PLCβ to Gβγ. Taken together, these findings provide a novel mechanism of regulating cell migration, i.e., RACK1-mediated interference with Gβγ-dependent activation of key effectors critical for chemotaxis.
Details
- Title: Subtitle
- RACK1 Regulates Directional Cell Migration by Acting on Gβγ at the Interface with Its Effectors PLCβ and PI3Kγ
- Creators
- Songhai Chen - Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; andFang Lin - Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; andMyung Eun Shin - Department of Cell and Developmental Biology, University of Illinois, Urbana, IL 61801Fei WangLixin Shen - Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; andHeidi E Hamm - Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; and
- Resource Type
- Journal article
- Publication Details
- Molecular biology of the cell, Vol.19(9), pp.3909-3922
- DOI
- 10.1091/mbc.e08-04-0433
- PMID
- 18596232
- PMCID
- PMC2526680
- NLM abbreviation
- Mol Biol Cell
- ISSN
- 1059-1524
- eISSN
- 1939-4586
- Publisher
- American Society for Cell Biology
- Language
- English
- Date published
- 09/2008
- Academic Unit
- Anatomy and Cell Biology; Iowa Neuroscience Institute; Craniofacial Anomalies Research Center; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040537302771
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