IL7:p-Y449-IL7R:JAK1:IL2RG:JAK3 binds PI3K regulatory subunits

Inferred from mouse: <br>The p85 subunit of PI3-kinase (PI3K) binds to phosphorylated Tyrosine-449 (Y449) on IL7R. <br>Y449F substitution inhibits PI3K-dependent proliferation of IL7-stimulated murine B-lineage cells (Venkitaraman & Cowling 1994). Stimulation of human lymphocyte precursor cells with IL7 induced tyrosine phosphorylation of the p85 subunit of PI3K and activation of PI3K kinase activity (Dadi et al. 1994). It is thought that, depending on species differences and stage of lymphocyte development, IL7 induced PI3K pathway can promote signals that are important for survival and proliferation of both T cells and B cells. Activation of PI3K leads to the generation of membrane associated PIP3 and membrane recruitment of AKT/PKB, the key downstream target of PI3K. AKT mediates phosphorylation of downstream substrates involved in regulation of cell survival and proliferation. IL7 induced activation of PI3K/AKT in human thymocytes has been reported (Pallard et al. 1999; Johnson et al. 2008). In mouse thymocytes IL7 stimulation resulted in the inactivation of BAD by serine phosphorylation; the PI3K/AKT pathway has been implicated in BAD phosphorylation. These results suggest that IL7 signaling via AKT inactivates the pro-apoptotic protein BAD promoting T cell survival (Li et al. 2004). <br><br>Rochman et al. (2009) suggested that IL7 promotes lymphocyte survival by activating the pro-survival PI3K/AKT signaling pathway and by increasing the expression of survival factors such as BCL2 and myeloid cell leukemia sequence 1 (MCL-1) while inhibiting the expression of pro-apoptotic factors BAX and BAD.<br>Interleukin-7 induced PI3K-dependent phosphorylation of AKT1 (Akt1 or PKB) and its downstream targets GSK-3, FOXO1, and FOXO3a (Barata et al.2004).<br>

由小鼠推断：<br>PI3-激酶（PI3K）的p85亚基与IL7R上的磷酸化酪氨酸-449（Y449）结合。<br>Y449F替换抑制了由IL7刺激的鼠B系细胞中PI3K依赖性的增殖（Venkitaraman & Cowling 1994）。IL7对人淋巴细胞前体细胞的刺激导致PI3K的p85亚基发生酪氨酸磷酸化，并激活PI3K激酶活性（Dadi et al. 1994）。据推测，根据物种差异和淋巴细胞发育阶段的不同，IL7诱导的PI3K通路可以促进对T细胞和B细胞生存和增殖至关重要的信号。<br>PI3K的激活导致膜结合型PIP3的产生以及AKT/PKB（PI3K的关键下游靶点）的膜募集。AKT介导下游底物的磷酸化，这些底物参与细胞生存和增殖的调控。据报道，IL7诱导的人胸腺细胞中PI3K/AKT的激活（Pallard et al. 1999; Johnson et al. 2008）。在鼠胸腺细胞中，IL7刺激导致BAD通过丝氨酸磷酸化而失活；PI3K/AKT通路已被涉及BAD磷酸化。这些结果表明，IL7通过AKT信号通路激活失活促凋亡蛋白BAD，从而促进T细胞的生存（Li et al. 2004）。<br><br>Rochman等（2009）提出，IL7通过激活促生存的PI3K/AKT信号通路，并增加生存因子如BCL2和髓系细胞白血病序列1（MCL-1）的表达，同时抑制促凋亡因子BAX和BAD的表达，从而促进淋巴细胞生存。<br>IL-7诱导的AKT1（Akt1或PKB）及其下游靶点GSK-3、FOXO1和FOXO3a的PI3K依赖性磷酸化（Barata et al.2004）。