IL7R is phosphorylated on Y499

Interleukin-7 (IL7) signaling is believed to resemble that of other gammaC family receptors, based on detailed studies of the Interleukin-2 receptor. Extending this model to IL7 suggested a series of events that bring Tyrosine-protein kinase JAK1 (JAK1) and Tyrosine-protein kinase JAK3 (JAK3) into proximity within a complex IL7:IL7R:JAK1:IL2RG:JAK3. Cytoplasmic domains of the receptor chains re-orient so that their associated kinases (JAKs and possibly phosphatidylinositol 3-kinases) can phosphorylate sequence elements on the cytoplasmic domains (Jiang et al. 2005). Tyrosine-449 (Y449) in the cytoplasmic domain of Interleukin-7 receptor is required for T-cell development in vivo and for activation of the JAK/STAT5 and PI3K/Akt pathways (Jiang et al. 2004, Pallard et al. 1999). <br>It has been sugggested that JAK1 phosphorylates IL7R (Jiang et al. 2004) and it is believed that JAK3, associated with IL2RG, phosphorylates the tyrosine residues in the cytoplasmic portion of IL7R that lead to recruitment of STATs (Fry & Mackall 2002). This is consistent with the lack of intrinsic tyrosine kinase activity in IL7R:JAK1 in the absence of IL2RG:JAK3 (Lai et al. 1996). Phosphorylated Y449 is believed to be the docking site for STAT5 and possibly PI3K, which are then activated by JAKs (Lin et al. 1995, Jiang et al. 2004). T-cells from IL7R Y449F knock-in mice did not activate Signal transducer and activator of transcription A or B (STAT5A, STAT5B) (Osbourne et al. 2007), indicating that IL7 regulates STAT5 activity via this key tyrosine.

基于对白介素-2受体的深入研究，有理由相信白介素-7（IL7）的信号传导机制与γC家族受体的信号传导机制相似。将此模型扩展至IL7，提出了一系列事件，这些事件使得酪氨酸蛋白激酶JAK1（JAK1）和酪氨酸蛋白激酶JAK3（JAK3）在复杂的IL7:IL7R:JAK1:IL2RG:JAK3复合物中相互靠近。受体链的胞质域重新定向，以便其关联的激酶（JAKs以及可能的磷脂酰肌醇3激酶）能够在胞质域上的序列元素进行磷酸化（江等，2005）。白介素-7受体胞质域中的酪氨酸-449（Y449）对于T细胞的体内发育以及JAK/STAT5和PI3K/Akt通路的激活是必需的（江等，2004；Pallard等，1999）。已有研究表明，JAK1磷酸化IL7R（江等，2004），并且普遍认为与IL2RG关联的JAK3磷酸化IL7R胞质部分中的酪氨酸残基，从而导致STATs的募集（Fry与Mackall，2002）。这与IL7R:JAK1在缺乏IL2RG:JAK3时缺乏内在酪氨酸激酶活性是一致的（Lai等，1996）。人们认为磷酸化的Y449是STAT5以及可能的PI3K的结合位点，这些蛋白随后被JAKs激活（Lin等，1995；江等，2004）。来自IL7R Y449F敲入小鼠的T细胞未能激活信号转导和转录激活因子A或B（STAT5A，STAT5B）（Osbourne等，2007），这表明IL7通过这一关键酪氨酸调节STAT5的活性。