The JAK-STAT Pathway: Signal Transduction Involved in Proliferation, Differentiation and Transformation

STAT proteins become activated upon tyrosine and serine phosphorylation, are subsequently translocated from the cytosol to the nucleus where they exert DNA-binding activity. Several STAT binding consensus motifs have been identified in the promoters of distinct genes. These consensus elements mediate STAT recruitment and influence the kind of STAT proteins that are bound at a specific promoter site. Recent structure function analyses have revealed conserved amino terminal sequences to be crucial for phosphatase dependent deactivation of the STAT proteins. To date an increasing amount of data is available concerning the on- and off-regulation of STAT activity. Considerable convergence as well as crosstalk has been shown between the JAK-STAT pathway and the MAPK, RAS, PI3K, PKC, and PKA involving pathways. Moreover, the nature of the genes that are regulated by STAT proteins as well as the cell functions that result from STAT activation are of great current interest. Understanding the critical functional role of STAT mediated signalling events as well as their regulation by interfering pathways provides new insights into the mechanisms involved in malignant cell proliferation.