A NEW-PROTEIN CONTAINING AN SH2 DOMAIN THAT INHIBITS JAK KINASES

The proliferation and differentiation of cells of many Lineages are re gulated by secreted proteins known as cytokines. Cytokines exert their biological effect through binding to cell-surface receptors that are associated with one or more members of the JAK family of cytoplasmic t yrosine kinases. Cytokine-induced receptor dimerization leads to the a ctivation of JAKs, rapid tyrosine-phosphorylation of the cytoplasmic d omains, and subsequent recruitment of various signalling proteins, inc luding members of the STAT family of transcription factors, to the rec eptor complex(1-5). Using the yeast two-hybrid system, we have now iso lated a new SH2-domain-containing protein, TAB, which is a JAK-binding protein that interacts with the Jak2 tyrosine-kinase JH1 domain(6). J AB is structurally related to CIS, a cytokine-inducible SH2 protein(7, 8). Interaction of JAB with Jak1, Jak2 or Jak3 markedly reduces their tyrosine-kinase activity and suppresses the tyrosine-phosphorylation a nd activation of STATs. TAB and CIS appear to function as negative reg ulators in the JAK signalling pathway.