神经纤维蛋白1
生物
磷酸化
蛋白激酶C
细胞生物学
表皮生长因子
丝氨酸
信号转导
激酶
细胞培养
癌症研究
分子生物学
神经纤维瘤病
遗传学
作者
Dimitra Mangoura,Yonglian Sun,C Li,Deepak Singh,David H. Gutmann,Alex F. C. Flores,Maqbool Ahmed,George Vallianatos
出处
期刊:Oncogene
[Springer Nature]
日期:2005-11-28
卷期号:25 (5): 735-745
被引量:77
标识
DOI:10.1038/sj.onc.1209113
摘要
Children with neurofibromatosis (NF1) typically develop central nervous system (CNS) abnormalities, including aberrant proliferation of astrocytes and formation of benign astrocytomas. The NF1 gene encodes neurofibromin, a Ras-GAP, highly expressed in developing neural cells; the mechanism of regulation of neurofibromin as a Ras-GAP, remains however unknown. We now show that, in response to EGF, neurofibromin is in vivo phosphorylated on serine residues by PKC-alpha, in human, rat, and avian CNS cells and cell lines. EGF-induced PKC phosphorylation was prominent in the cysteine/serine-rich domain (CSRD) of neurofibromin, which lies in the N-terminus and upstream of the Ras-GAP domain (GRD), and this modification significantly increased the association of neurofibromin with actin in co-immunoprecipitations. In addition, we show that Ras activation in response to EGF was significantly lowered when C62B cells overexpressed a construct encoding both CSRD + GRD. Moreover, when PKC-alpha was downregulated, the Ras-GAP activity of CSRD + GRD was significantly diminished, whereas overexpressed GRD alone acted as a weaker GAP and in a PKC-independent manner. Most importantly, functional Ras inhibition and EGF signaling shifts were established at the single cell level in C6-derived cell lines stably overexpressing CSRD + GRD, when transient co-overexpression of Ras and PKC-depletion prior to stimulation with EGF-induced mitosis. Taken together, these data provide the first evidence of a functional, allosteric regulation of GRD by CSRD, which requires neurofibromin phosphorylation by PKC and association with the actin cytoskeleton. Our data may suggest a novel mechanism for regulating biological responses to EGF and provide a new aspect for the understanding of the aberrant proliferation seen in the CNS of children with NF1.
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