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Molecular and Cellular Biology, March 2001, p. 1795-1809, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1795-1809.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Protein Tyrosine Phosphatase phi  Regulates Paxillin Tyrosine Phosphorylation and Mediates Colony-Stimulating Factor 1-Induced Morphological Changes in Macrophages

Fiona J. Pixley,1 Pierre S. W. Lee,1 John S. Condeelis,2 and E. Richard Stanley1,*

Department of Developmental and Molecular Biology1 and Department of Anatomy and Structural Biology and the Analytical Imaging Facility,2 Albert Einstein College of Medicine, Bronx, New York 10461

Received 11 September 2000/Returned for modification 25 October 2000/Accepted 1 December 2000

Removal of colony-stimulating factor 1 (CSF-1) causes macrophages to round up and to increase their expression of protein tyrosine phosphatase phi  (PTPphi ). This is accompanied by the disruption of focal complexes and the formation of ruffles. Here we have overexpressed wild-type (WT) PTPphi and a phosphatase-inactive (C325S) mutant in a macrophage cell line in the presence and absence of CSF-1. In the presence of CSF-1, WT PTPphi induces cell rounding and ruffle formation, while C325S PTPphi has no effect. In contrast, in CSF-1-starved cells, C325S PTPphi behaves in a dominant negative fashion, preventing rounding and ruffling. Furthermore, C325S PTPphi increases adhesion in cycling cells, while WT PTPphi enhances motility. In WT PTPphi -overexpressing cells, the focal contact protein paxillin is selectively depleted from focal complexes and specifically dephosphorylated on tyrosine. In contrast, paxillin is hyperphosphorylated in C325S PTPphi -expressing cells. Moreover, a complex containing PTPphi , paxillin, and a paxillin-associated tyrosine kinase, Pyk2, can be immunoprecipitated from macrophage lysates, and the catalytic domain of PTPphi selectively binds paxillin and Pyk2 in vitro. Although PTPphi and Pyk2 do not colocalize with paxillin in focal complexes, all three proteins are colocalized in dorsal ruffles. The results suggest that paxillin is dephosphorylated by PTPphi in dorsal ruffles, using Pyk2 as a bridging molecule, resulting in a reduced pool of tyrosine-phosphorylated paxillin available for incorporation into focal complexes, thereby mediating CSF-1 regulation of macrophage morphology, adhesion, and motility.

* Corresponding author. Mailing address: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461. Phone: (718) 430-2344. Fax: (718) 430-8567. E-mail: rstanley{at}aecom.yu.edu.

Molecular and Cellular Biology, March 2001, p. 1795-1809, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1795-1809.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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