The M-CSF receptor substrate and interacting protein FMIP is governed in its subcellular localization by protein kinase C-mediated phosphorylation, and thereby potentiates M-CSF-mediated differentiation
The M-CSF receptor substrate and interacting protein FMIP is governed in its subcellular localization by protein kinase C-mediated phosphorylation, and thereby potentiates M-CSF-mediated differentiation
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DOI：
10.1038/sj.onc.1207841
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发表时间：
2004-08-26
期刊：
影响因子：
8
通讯作者：
Tamura, T
中科院分区：
文献类型：
--
作者：
Mancini, A;Koch, A;Tamura, T
巨噬细胞集落刺激因子(M-CSF或CSF-1)及其同源受体酪氨酸激酶c-FMS是单核细胞和巨噬细胞发育所必需的。我们最近发现了一种FMS相互作用蛋白(FMIP)，它瞬时结合到激活的FMS分子的细胞质结构域，并被FMS酪氨酸激酶在酪氨酸上磷酸化。FMIP不仅是FMS的底物，也是蛋白激酶C(PKC)的底物。突变研究表明，这发生在丝氨酸5和6上。邻近这些位点的是一个核定位信号(NLS)。我们表明，这种NLS对于FMIP的主要核定位是必不可少的。丝氨酸残基5和6上的仿磷取代的产生证实了PKC介导的该位点的磷酸化导致FMIP移位到胞浆。此外，突变的FMIP(FMIPSS5，6AA)即使在活化的PKCalpha存在的情况下也能在细胞核中大量检测到。野生型FMIP和FMIPSS5，6AA抑制M-CSF介导的生存信号，而表达FMIPSS5，6EE的细胞在M-CSF或TPA存在下比野生型细胞更有效地存活和分化为巨噬细胞。我们认为，M-CSF介导的PKCalpha激活可以增强FMIP启动生存/分化信号的作用。
Macrophage colony-stimulating factor (M-CSF or CSF-1) and its cognate receptor, the tyrosine kinase c-fms, are essential for monocyte and macrophage development. We have recently identified an Fms-interacting protein (FMIP) that binds transiently to the cytoplasmic domain of activated Fms molecules and is phosphorylated on tyrosine by Fms tyrosine kinase. FMIP is a substrate not only for Fms but also for protein kinase C (PKC). Mutagenesis reveals that this occurs on serines 5 and 6. Adjacent to these sites is a nuclear localization signal (NLS). We show that this NLS is essential for the predominantly nuclear localization of FMIP. Generation of phosphomimetic substitutions on serine residues 5 and 6 confirms that PKC-mediated phosphorylation on this site leads to translocation of FMIP to the cytosol. Furthermore, the mutant FMIP (FMIPSS5,6AA) was detected abundantly in the nucleus even in the presence of activated PKCalpha. Wild-type FMIP and FMIPSS5,6AA inhibited M-CSF-mediated survival signaling, while FMIPSS5,6EE-expressing cells survived and differentiated into macrophages more efficiently than wild-type cells in the presence of M-CSF or TPA. We conclude M-CSF-mediated activation of PKCalpha can potentiate FMIP action to initiate survival/differentiation signaling.