Reddy E P, Korapati A, Chaturvedi P, Rane S
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 N Broad Street, Philadelphia, Pennsylvania, PA 19140, USA.
Oncogene. 2000 May 15;19(21):2532-47. doi: 10.1038/sj.onc.1203594.
Hematopoiesis is the cumulative result of intricately regulated signal transduction cascades that are mediated by cytokines and their cognate receptors. Proper culmination of these diverse signaling pathways forms the basis for an orderly generation of different cell types and aberrations in these pathways is an underlying cause for diseases such as cancer. Over the past several years, downstream events initiated upon cytokine/growth factor stimulation have been a major focus of biomedical research. As a result, several key concepts have emerged allowing a better understanding of the complex signaling processes. A group of novel transcription factors, termed signal transducers and activators of transcription (STATs) appear to orchestrate the downstream events propagated by cytokine/growth factor interactions with their cognate receptors. Until recently, the JAK proteins were considered to be the tyrosine kinases, which dictated the levels of phosphorylation and activation of STAT proteins, forming the basis of the JAK-STAT model. However, over the past few years, increasing evidence has accumulated which indicates that at least some of the STAT protein activation may be mediated by members of the Src gene family following cytokine/growth factor stimulation. Studies have demonstrated that the Src-family of tyrosine kinases can phosphorylate and activate certain STAT proteins, in lieu of JAK kinases. In such a scenario, JAK kinases may be more crucial to phosphorylation of the cytokine/growth factor receptors and in the process create docking sites on the receptors for binding of SH2-containing proteins such as STATs, Src-kinases and other signaling intermediates. Tyrosine phosphorylation and activation of STAT proteins can be achieved either by JAKs or Src-kinases depending on the nature of STAT that is being activated. This forms the basis for the JAK-Src-STAT model proposed in this review. The concerted action of JAK kinases, members of the Src-kinase family and STAT proteins, leads to cell proliferation and cell survival, the end-point of the cytokine/growth factor stimulus. Oncogene (2000).
造血作用是由细胞因子及其同源受体介导的复杂调控信号转导级联反应的累积结果。这些不同信号通路的正确 culmination 为有序生成不同细胞类型奠定了基础，而这些通路中的异常是癌症等疾病的根本原因。在过去几年中，细胞因子/生长因子刺激引发的下游事件一直是生物医学研究的主要焦点。因此，出现了几个关键概念，有助于更好地理解复杂的信号传导过程。一组称为信号转导和转录激活因子（STATs）的新型转录因子似乎在协调由细胞因子/生长因子与其同源受体相互作用所传播的下游事件。直到最近，JAK 蛋白被认为是酪氨酸激酶，它决定了 STAT 蛋白的磷酸化和激活水平，构成了 JAK-STAT 模型的基础。然而，在过去几年中，越来越多的证据表明，至少某些 STAT 蛋白的激活可能在细胞因子/生长因子刺激后由 Src 基因家族成员介导。研究表明，酪氨酸激酶的 Src 家族可以磷酸化并激活某些 STAT 蛋白，以替代 JAK 激酶。在这种情况下，JAK 激酶可能对细胞因子/生长因子受体的磷酸化更为关键，并在此过程中在受体上创建用于结合含 SH2 蛋白（如 STATs、Src 激酶和其他信号中间体）的对接位点。根据被激活的 STAT 的性质，STAT 蛋白的酪氨酸磷酸化和激活可以通过 JAKs 或 Src 激酶来实现。这构成了本综述中提出的 JAK-Src-STAT 模型的基础。JAK 激酶、Src 激酶家族成员和 STAT 蛋白的协同作用导致细胞增殖和细胞存活，这是细胞因子/生长因子刺激的终点。《癌基因》（2000 年）
