JAKs, STATs and Src kinases in hematopoiesis

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 dierent cell types and aberrations in these pathways is an underlying cause for diseases such as leukemias and other myeloproliferative and lymphoproliferative disorders. Over the past decade, downstream signal transduction events initiated upon cytokine/growth factor stimulation have been a major focus of basic and applied biomedical research. As a result, several key concepts have emerged allowing a better understanding of the complex signaling processes. A group of 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. Similarly, cytoplasmic Janus protein tyrosine kinases (JAKs) and Src family of kinases seem to play a critical role in diverse signal transduction pathways that govern cellular survival, proliferation, dierentiation and apoptosis. Accumulating evidence suggests that STAT protein activation may be mediated by members of both JAK and Src family members following cytokine/growth factor stimulation. In addition, JAK kinases appear to be essential for the phosphorylation of the cytokine receptors which results in the creation of docking sites on the receptors for binding of SH2-containing proteins such as STATs, Src-kinases and other signaling intermediates. Cell and tissue-speci®city of cytokine action appears to be determined by the nature of signal transduction pathways activated by cytokine/receptor interactions. The integration of these diverse signaling cues from active JAK kinases, members of the Srcfamily kinases and STAT proteins, leads to cell proliferation, cell survival and dierentiation, the endpoint of the cytokine/growth factor stimulus.

Inhibition of activated STAT5 in Bcr/Abl expressing leukemia cells with new pimozide derivatives

“…STATs are activated into the cytosol by phosphorylation of specific tyrosine residues forming homo-or heterodimers that enter into the nucleus and bind to the specific DNA sequences in the promoter regions of various genes involved in cell survival, proliferation and differentiation. 1 STAT5 protein consists of a N-terminal domain that is involved in promoting STAT5 dimerization, a DNA binding domain that interacts with a conserved DNA binding sequence, an SH2 domain that drives the initial interaction of STAT5 protein with phosphorylated tyrosine residues in the cytoplasmic tails of cytokine receptors, and a C-terminal transactivation domain. 2 In order to be functional, STAT5 proteins must first be activated.…”

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

“…The unique structure of the JAKs clearly separates them from other members of the protein tyrosine kinase family [92], (Fig. 3).…”

Signal transduction pathways that contribute to myeloid differentiation

“…[28][29][30][31][32] The binding of cytokines or growth factors to their cognate receptors leads to receptor oligomerization and subsequent activation of kinase signaling by the receptor cytoplasmic domain 33 or by receptor-associated tyrosine kinases including the JAKs 34 or Src family kinases 35 (SFKs). Activation of this kinase signaling leads to direct tyrosine phosphorylation of STAT proteins followed by STAT dimerization.…”