STRUCTURAL AND MECHANISTIC ASPECTS OF JANUS KINASES - HOW THE 2-FACEDGOD WIELDS A DOUBLE-EDGED-SWORD

The Janus family of protein-tyrosine kinases has long been known to fu nction in signal transduction pathways initiated by a host of cytokine s, A brief overview of the role of Janus kinases (Jaks) in both cytoki ne and noncytokine signaling pathways highlights the broad physiologic importance of this kinase family, New insights into the structural an d mechanistic regulatory aspects of Janus kinases are rapidly emerging , Recent mutational analyses allow the dissection of Jaks into three d istinct structural domains governing receptor affiliation, autoregulat ion, and catalysis, A fourth domain determining substrate specificity is as yet poorly defined and is, therefore, discussed in the context o f known substrates and inhibitors, a collection of molecules that have been expanded recently to include Stam and Jab, The proposed mechanis m of the interconversion of Janus kinases from inactive to fully activ e enzymes involves three states of enzymatic activity, Additional laye rs of regulation can be independently superimposed on this multistate model, providing a simplified description of the behavior of Janus kin ases under normal and pathologic circumstances.