The p85 regulatory subunit controls sequential activation of phosphoinositide 3-kinase by Tyr kinases and Ras
The p85 regulatory subunit controls sequential activation of phosphoinositide 3-kinase by Tyr kinases and Ras
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DOI：
10.1074/jbc.m205893200
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发表时间：
2002-11-01
影响因子：
4.8
通讯作者：
Carrera, AC
中科院分区：
文献类型：
--
作者：
Jiménez, C;Hernández, C;Carrera, AC
IA类磷脂酰肌醇3-激酶（PI 3 K）是由p85调节亚基和p110催化亚基组成的异源二聚体，其调节多种细胞应答，包括细胞分裂和存活。PI 3 K在Tyr激酶刺激后被Ras激活。我们发现，p85的C-末端区域，包括C-Src同源2（C-SH 2）结构域和部分的间SH 2区域，保护p110催化亚基从Ras诱导的激活。虽然p110活性与C-末端p85缺失突变体的活性增加显着的活性形式的Ras的存在下，纯化的野生型p85-p110仅轻微刺激活性Ras。尽管如此，温育纯化的p85-p110与酪氨酸磷酸化肽，模拟活化的血小板衍生生长因子受体，恢复Ras诱导的p85-p110激活。总之，p85抑制Ras对p110的激活;这种阻断通过Tyr激酶刺激释放，表明Tyr激酶介导的IA类PI 3 K刺激的经典机制也调节Ras诱导的PI 3 K激活。
Class IA phosphoinositide 3-kinase (PI3K) is a heterodimer composed of a p85 regulatory and a p110 catalytic subunit that regulates a variety of cell responses, including cell division and survival. PI3K is activated following Tyr kinase stimulation and by Ras. We found that the C-terminal region of p85, including the C-Src homology 2 (C-SH2) domain and part of the inter-SH2 region, protects the p110 catalytic subunit from Ras-induced activation. Although the p110 activity associated with a C-terminal p85 deletion mutant increased significantly in the presence of an active form of Ras, purified wild type p85-p110 was only slightly stimulated by active Ras. Nonetheless, incubation of purified p85-p110 with Tyr-phosphorylated peptides, which mimic the activated platelet-derived growth factor receptor, restored Ras-induced p85-p110 activation. In conclusion, p85 inhibits p110 activation by Ras; this blockage is released by Tyr kinase stimulation, showing that the classical mechanism of class IA, PI3K stimulation mediated by Tyr kinases also regulates Ras-induced PI3K activation.