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

Abstract

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 di erent 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.

EGF receptor‐mediated, c‐Src‐dependent, activation of Stat5b is downregulated in mitogenically responsive hepatocytes

“…We also observed a basal tyrosine kinase activity in immunoprecipitates of c-Src from hepatocyte lysates, which was inhibited by CGP77675, but so far we have not found any significant increase of this kinase activity after EGF stimulation (data not shown). The data support the notion that although c-Src tyrosine kinase activity is required for EGF-induced Stat5b activation, this might reflect a cooperation between cSrc and the EGF receptor and not necessarily c-Src activation as a direct downstream effect of the EGF receptor (Biscardi et al, 1999;Abram and Courtneidge, 2000;Reddy et al, 2000;Garcia et al, 2001).…”

“…Src has also been reported to activate Stat5 (Kazansky et al, 1999;Reddy et al, 2000), and recent findings in A431 and HepG2 cells suggest that c-Src may be involved in EGF receptor-mediated activation of Stat5 (Olayioye et al, 1999;Wang et al, 1999), while PDGF-induced Stat5 activation was independent of c-Src and c-Fyn in some transfected cells and cell-free systems (Paukku et al, 2000). To examine the role of c-Src in the effect of EGF on Stat5b activation in the cultured hepatocytes, we preincubated the cells for 90 min with CGP77675, an inhibitor of the c-Src kinase (Missbach et al, 1999;Susa et al, 2000), prior to stimulation with an agonist.…”

Association study of CSF2RB with schizophrenia in Irish family and case – control samples

“…15 IL3 is a major component of immune system and plays a critical role in the development and differentiation of all hematopoietic cell types. 16,17 IL3 and other cytokines have been found to have neurotrophic activities and to be associated with neurologic disorders, [18][19][20][21] suggesting their complex role in the central nervous system (CNS). IL3 is one of the major factors that activate the microglia in the brain.…”

Interleukin 3 and schizophrenia: the impact of sex and family history

“…[10][11][12] Of particular interest is that IL3 can stimulate cell growth and suppress apoptosis. 13 Dysfunction of apoptosis may be involved in the pathophysiology of schizophrenia. 14 Abnormal activities of several interleukins, 15,16 including IL3, 17 have been observed in schizophrenia patients.…”