IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

Hematopoiesis is the cumulative result of intricately regulated signal tran sduction cascades that are mediated by cytokines and their cognate receptor s, Proper culmination of these diverse signaling pathways forms the basis f or an orderly generation of different cell types and aberrations in these p athways is an underlying cause for diseases such as cancer. Over the past s everal years, downstream events initiated upon cytokine/growth factor stimu lation have been a major focus of biomedical research. As a result, several hey concepts have emerged allowing a better understanding of the complex s ignaling processes, A group of novel transcription factors, termed signal t ransducers and activators of transcription (STATs) appear to orchestrate th e downstream events propagated by cytokine/growth factor interactions with their cognate receptors, Until recently, the JAK proteins were considered t o be the tyrosine kinases, which dictated the levels of phosphorylation and activation of STAT proteins, forming the basis of the JAK-STAT model. Howe ver, over the past few years, increasing evidence has accumulated which ind icates that at least some of the STAT protein activation may be mediated by members of the Src gene family following cytokine/growth factor stimulatio n. Studies have demonstrated that the Src-family of tyrosine kinases can ph osphorylate 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-ki nases and other signaling intermediates, Tyrosine phosphorylation and activ ation of STAT proteins can be achieved either by JAKs or Src-kinases depend ing 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 JA K kinases, members of the Src-kinase family and STAT proteins, leads to cel l proliferation and cell survival, the end-point of the cytokine/growth fac tor stimulus.