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J. Biol. Chem., Vol. 276, Issue 13, 10212-10217, March 30, 2001
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From the Departments of 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)
CD45 Negatively Regulates Monocytic Cell Differentiation by
Inhibiting Phorbol 12-Myristate 13-Acetate-dependent
Activation and Tyrosine Phosphorylation of Protein Kinase C
*
,,,, and§¶
Animal Sciences and
§ Pathology, University of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
.
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
PKC activation. Importantly, PMA-dependent tyrosine
phosphorylation of PKC was also increased 4-fold in CD45as cells.
Finally, inhibitors of MEK (PD98059) and PKC (rottlerin) completely
blocked PMA-induced monocytic cell differentiation. Taken together,
these data indicate that CD45 inhibits PMA-dependent PKC
activation by impeding PMA-dependent PKC tyrosine
phosphorylation. Furthermore, this blunting of PKC activation leads
to an inhibition of PKC-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.
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