JAK AND STAT PROTEINS IN CELLULAR SIGNAL- TRANSDUCTION

Understanding of the JAK/STAT signaling pathway has greatly expanded o ver the past few years. JAK/STAT signaling is based on the activation by tyrosine phosphorylation of STAT proteins, otherwise present in a l atent state in the cytoplasm. STAT activation leads to the formation o f STAT dimers and their migration to the nucleus where they can enhanc e transcription of specific target genes. The double capability of the STATs to respond to extracellular stimuli and to activate transcripti on gave the rationale for their name of ''Signal Transducers and Activ ators of Transcription''. Protein tyrosine kinases of the Janus kinase family, or JAKs, play a direct role in STAT activation by cytokine re ceptors. The mechanism of STAT1 activation by the interferon gamma rec eptor was proposed as a paradigm for JAK/STAT signaling pathways. Spec ificity in the signaling appears to be achieved gradually through succ essive steps starting with the binding of a specific ligand to its rec eptor and culminating with specific interactions among transcriptions factors which lead to transcriptional activation. In addition to the r ole of tyrosine phosphorylation for JAK/STAT signaling, JAKs and STATs appear to be implicated in signaling pathways involving protein serin e kinases. The extensive interest in the JAK/STAT signaling pathways a rises from the pleiotropy of effects, such as cellular proliferation o r immune function, that these pathways appear to control. In addition, the fact that pathologies such as leukemia or immune deficiencies wer e recently found to be closely linked to deregulation of JAK/STAT sign aling pathways promoted a renewed interest in the field and opened per spectives for gene therapy research.