CD45 negatively regulates monocytic cell differentiation by inhibiting phorbol 12-myristate 13-acetate-dependent activation and tyrosine phosphorylation of protein kinase Cδ
CD45 negatively regulates monocytic cell differentiation by inhibiting phorbol 12-myristate 13-acetate-dependent activation and tyrosine phosphorylation of protein kinase Cδ
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DOI：
10.1074/jbc.m010589200
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发表时间：
2001-03-30
影响因子：
4.8
通讯作者：
Freund, GG
中科院分区：
文献类型：
--
作者：
Deszo, EL;Brake, DK;Freund, GG
蛋白酪氨酸磷酸酶CD45在所有单核细胞上都有表达，但其在这些细胞中的功能尚不清楚。在此，我们报道CD45通过抑制佛波醇12-肉豆蔻酸盐13-醋酸酯(PMA)依赖的蛋白激酶C(PKC)增量的激活来负向调节单核细胞的分化。我们发现，在U937单核细胞(CD45AS细胞)中反义CD45的减少使PMA扩大细胞体积、增加细胞质突起的宽度和长度以及诱导CD11b的表面表达的能力增加100%。此外，CD45表达的降低导致PMA诱导的MEK和细胞外信号调节激酶(ERK)1/2活性高峰的持续时间从5min延长到30min，同时导致PMA依赖的PKC Delta激活增加4倍。重要的是，在CD45AS细胞中，依赖PMA的PKC Delta的酪氨酸磷酸化也增加了4倍。最后，MEK(PD98059)和PKC Delta(Rotlerin)的抑制剂完全阻断了PMA诱导的单核细胞分化。综上所述，这些数据表明，CD45通过抑制PMA依赖的PKC Delta的酪氨酸磷酸化来抑制依赖PMA的PKC Delta的激活，此外，这种钝化PKC Delta的激活导致抑制依赖PKC Delta的ERK1/2和依赖ERK1/2的单核细胞分化。这些发现表明CD45是单核细胞发育的关键调节因子。
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 PKC delta activation. Importantly, PMA-dependent tyrosine phosphorylation of PKC delta was also increased 4-fold in CD45as cells. Finally, inhibitors of MEK (PD98059) and PKC delta (rottlerin) completely blocked PMA-induced monocytic cell differentiation. Taken together, these data indicate that CD45 inhibits PMA-dependent PKC delta activation by impeding PMA-dependent PKC delta tyrosine phosphorylation, Furthermore, this blunting of PKC delta activation leads to an inhibition of PKC delta -dependent activation of ERK1/2 and ERK1/2-dependent monocyte differentiation. These findings suggest that CD45 is a critical regulator of monocytic cell development.