1282 tandem kinase-homologous domains at the C-terminus. The first is a noncatalytic regulatory domain, whereas the second has tyrosine kinase activity. In mammals, the JAK family comprises four members: JAK1, JAK2, JAK 3 and Tyk2. JAK activation occurs upon ligand-mediated receptor multimerization because two JAKs are brought into close proximity, allowing trans-phosphorylation. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs. STATs are latent transcription factors that reside in the cytoplasm until activated. The seven mammalian STATs bear a conserved tyrosine residue near the C-terminus that is phosphorylated by JAKs. This phosphotyrosine permits the dimerization of STATs through interaction with a conserved SH2 domain. Phosphorylated STATs enter the nucleus by a mechanism that is dependent on importin α-5 (also called nucleoprotein interactor 1) and the Ran nuclear import pathway. Once in the nucleus, dimerized STATs bind specific regulatory sequences to activate or repress transcription of target genes. Thus the JAK/STAT cascade provides a direct mechanism to translate an extracellular signal into a transcriptional response.

In addition to the principal components of the pathway, other effector proteins have been identified that contribute to at least a subset of JAK/STAT signaling events. STAMs (signal-transducing adapter molecules) are adapter molecules with conserved VHS and SH3 domains (Lohi and Lehto, 2001). STAM1 and STAM2A can be phosphorylated by JAK1-JAK3 in a manner that is dependent on a third domain present in some STAMs, the ITAM (inducible tyrosine-based activation motif). Through a poorly understood mechanism, the STAMs facilitate the transcriptional activation of specific target genes, including MYC. A second adapter that facilitates JAK/STAT pathway activation is StIP (stat-interacting protein), a WD40 protein. StIPs can associate with both JAKs and unphosphorylated STATs, perhaps serving as a scaffold to facilitate the phosphorylation of STATs by JAKs. A third class of adapter with function