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Originally published In Press as doi:10.1074/jbc.M010589200 on December 21, 2000

J. Biol. Chem., Vol. 276, Issue 13, 10212-10217, March 30, 2001
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CD45 Negatively Regulates Monocytic Cell Differentiation by Inhibiting Phorbol 12-Myristate 13-Acetate-dependent Activation and Tyrosine Phosphorylation of Protein Kinase Cdelta *

Eric L. DeszoDagger , Danett K. BrakeDagger , Keith A. CengelDagger , Keith W. KelleyDagger , and Gregory G. FreundDagger §

From the Departments of Dagger  Animal Sciences and § Pathology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

The protein-tyrosine phosphatase CD45 is expressed on all monocytic cells, but its function in these cells is not well defined. Here we report that CD45 negatively regulates monocyte differentiation by inhibiting phorbol 12-myristate 13-acetate (PMA)-dependent activation of protein kinase C (PKC) delta . We found that antisense reduction of CD45 in U937 monocytic cells (CD45as cells) increased by 100% the ability of PMA to enlarge cell size, increase cell cytoplasmic process width and length, and induce surface expression of CD11b. In addition, reduction in CD45 expression caused the duration of peak PMA-induced MEK and extracellular signal-regulated kinase (ERK) 1/2 activity to increase from 5 min to 30 min while leading to a 4-fold increase in PMA-dependent PKCdelta activation. Importantly, PMA-dependent tyrosine phosphorylation of PKCdelta was also increased 4-fold in CD45as cells. Finally, inhibitors of MEK (PD98059) and PKCdelta (rottlerin) completely blocked PMA-induced monocytic cell differentiation. Taken together, these data indicate that CD45 inhibits PMA-dependent PKCdelta activation by impeding PMA-dependent PKCdelta tyrosine phosphorylation. Furthermore, this blunting of PKCdelta activation leads to an inhibition of PKCdelta -dependent activation of ERK1/2 and ERK1/2-dependent monocyte differentiation. These findings suggest that CD45 is a critical regulator of monocytic cell development.


* This work was supported by grants from the National Institutes of Health Grant (CA-61931 to G.G.F. and AG06246 to K.W.K.), The Macula Foundation (to G.G.F), the American Diabetes Association (to G.G.F.) and USDA/CREES (to G.G.F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence and reprint requests should be addressed: Dept. of Pathology, College of Medicine, 506 S. Mathews Ave., University of Illinois at Urbana-Champaign, Urbana, IL 61801. Tel.: 217-244-8839; Fax: 217-244-5617; E-mail: freun@ux1.cso.uiuc.edu.


Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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