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Molecular and Cellular Biology, April 2006, p. 2857-2868, Vol. 26, No. 7
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.7.2857-2868.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Glycogen Synthase Kinase 3- and Extracellular Signal-Regulated Kinase-Dependent Phosphorylation of Paxillin Regulates Cytoskeletal Rearrangement

Xinming Cai,1 Min Li,2 Julie Vrana,2 and Michael D. Schaller1,3,4*

Department of Cell and Developmental Biology,1 Lineberger Comprehensive Cancer Center,3 Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,4 Signal Transduction Group, Biosource International, Hopkinton, Massachusetts 017482

Received 25 May 2005/ Returned for modification 29 June 2005/ Accepted 10 January 2006

Paxillin is a 68-kDa focal adhesion-associated protein that plays an important role in controlling cell spreading and migration. Phosphorylation of paxillin regulates its biological activity and thus has warranted investigation. Serine 126 and serine 130 were previously identified as two major extracellular signal-regulated kinase (ERK)-dependent phosphorylation sites in Raf-transformed fibroblasts. Here serine 126 is identified as a phosphorylation site induced by lipopolysaccharide (LPS) stimulation of RAW264.7 cells. A number of other stimuli, including adhesion and colony-stimulating factor, induce serine 126 phosphorylation in RAW264.7 cells, and nerve growth factor (NGF) treatment induces serine 126 phosphorylation in PC12 cells. The kinase responsible for phosphorylation of this site is identified as glycogen synthase kinase 3 (GSK-3). Interestingly, this GSK-3-dependent phosphorylation is regulated via an ERK-dependent priming mechanism, i.e., phosphorylation of serine 130. Phosphorylation of S126/S130 was required to promote spreading in paxillin null cells, and LPS-induced spreading of RAW264.7 cells was inhibited by expression of the paxillin S126A/S130A mutant. Furthermore, this mutant also retarded NGF-induced PC12 cell neurite outgrowth. Hence, phosphorylation of paxillin on serines 126 and 130, which is mediated by an ERK/GSK-3 dual-kinase mechanism, plays an important role in cytoskeletal rearrangement.

* Corresponding author. Mailing address: Department of Cell & Developmental Biology, 534 Taylor Hall, CB # 7090, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Phone: (919) 966-0391. Fax: (919) 966-1856. E-mail: crispy4{at}med.unc.edu.

Molecular and Cellular Biology, April 2006, p. 2857-2868, Vol. 26, No. 7
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.7.2857-2868.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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