CD45 Negatively Regulates Monocytic Cell Differentiation by Inhibiting Phorbol 12-Myristate 13-Acetate-dependent Activation and Tyrosine Phosphorylation of Protein Kinase Cδ

Eric L. Deszo, Danett K. Brake, Keith A. Cengel, Keith W. Kelley, Gregory G. Freund

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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) δ. 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 PKCδ activation. Importantly, PMA-dependent tyrosine phosphorylation of PKCδ was also increased 4-fold in CD45as cells. Finally, inhibitors of MEK (PD98059) and PKCδ (rottlerin) completely blocked PMA-induced monocytic cell differentiation. Taken together, these data indicate that CD45 inhibits PMA-dependent PKCδ activation by impeding PMA-dependent PKCδ tyrosine phosphorylation. Furthermore, this blunting of PKCδ activation leads to an inhibition of PKCδ -dependent activation of ERK1/2 and ERK1/2-dependent monocyte differentiation. These findings suggest that CD45 is a critical regulator of monocytic cell development.

    Original languageEnglish (US)
    Pages (from-to)10212-10217
    Number of pages6
    JournalJournal of Biological Chemistry
    Volume276
    Issue number13
    DOIs
    StatePublished - Mar 30 2001

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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