Molecular analysis of proliferative signal transduction by cytokine

IL-2信号通过由α、β和伽马链组成的IL-2受体复合体传递。至少有三条信号通路与IL-2R有关：src家族PTK家族连接的c-fos/c-jun诱导通路、c-myc诱导通路和bcl2诱导通路。所有这些途径对IL-2的增殖信号都是必不可少的，因为这三个途径相互协作，以确保在IL-2刺激后的全方位信号传递。人T细胞白血病病毒I型(HTLV-I)是成人T细胞白血病(ATL)的病原体。尽管由HTLV-1编码的p40Tax-1可以激活病毒和细胞基因的转录，但p40Tax-1促进急性淋巴细胞性白血病发生的机制(S)尚不完全清楚。在本研究中，我们提供了证据，p40Tax-1可以与激活形式的p56lck或c-Myc协同促进IL-2或IL-3(IL-3)非依赖性增殖。最近，我们发现蛋白酪氨酸磷酸酶SHP-2是由IL-2刺激引起的酪氨酸磷酸化。IL-2Rβ的S区和A区是SHP-2磷酸化和src家族激酶所必需的，Lyn在这一事件中起重要作用。白细胞介素2受体(IL-2R)与JAK1和JAK3PTKs相关，配体诱导这些PTKs的激活对淋巴细胞增殖至关重要。最近，非受体PTK，PYK2，被发现在IL-2刺激后以Jak依赖的方式被激活。此外，还发现内源性PYK2和JAK3之间存在物理关联，并且PYK2的显性干扰突变体抑制了IL-2诱导的细胞增殖，但不影响Stat5的激活。综上所述，这些结果表明，Pyk2是Jak介导的IL-2信号通路中一个新发现的成分。

IL-2 signal is transmitted by IL-2 receptor complex composed of alpha, beta and gamma chains. At least three signaling pathways have been demonstrated to be linked to the IL-2R ; the src-family PTK-linked c-fos/c-jun induction pathway, the c-myc induction pathway, and the bcl-2 induction pathway. All of these pathways are essential for IL-2 proliferative signaling, since these three pathways cooperate with each other to ensure a full range of signal transmission following IL-2 stimulation. Human T cell leukemia virus type I(HTLV-I)is the etiologic agent of adult T cell leukemia(ATL). Although p40tax-1, which is encoded by HTLV-1, activates transcription of viral and cellular genes, the mechanism(s)by which p40tax-1 promotes leukemogenesis in ATL is not fully understood. In the present study, we provide evidence that p40tax-1 can cooperate with the activated form (lck F505)of p56lck, or c-Myc but not with Bcl-2 to promote IL-2 or interleukin3(IL-3)-independent proliferation. Recently, we have shown that protein-tyrosine phosphatase SHP-2 is tyrosine phosphorylated by IL-2 stimulation. S-region and A-region of IL-2R beta is required for SHP-2 phosphorylation and src-family kinase, Lyn is important for this event.The interleukin-2 receptor(IL-2R)is associated with the Jak1 and Jak3 PTKs, and ligand-induced activation of these PTKs is essential for lymphocyte proliferation. Recently, the non-receptor PTK,Pyk2, was found to be activated following IL-2 stimulation in a Jak-dependent manner. Furthermore, physical association was detected between endogenous Pyk2 and Jak3, and a dominant interfering mutant of Pyk2 inhibited IL-2-induced cell proliferation without affecting Stat5 activation. Collectively, these results suggest that Pyk2 is a newly identified component of the Jak-mediated IL-2 signalling pathway.