The proliferation and differentiation of cells of many Lineages are regulated 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 tyrosine kinases. Cytokine-induced receptor dimerization leads to the activation of JAKs, rapid tyrosine-phosphorylation of the cytoplasmic domains, and subsequent recruitment of various signalling proteins, including members of the STAT family of transcription factors, to the receptor complex(1-5). Using the yeast two-hybrid system, we have now isolated a new SH2-domain-containing protein, TAB, which is a JAK-binding protein that interacts with the Jak2 tyrosine-kinase JH1 domain(6). JAB 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 and activation of STATs. TAB and CIS appear to function as negative regulators in the JAK signalling pathway.