Janus Kinases and Cytokine Receptors

Abstract

Cytokines, present either in localized tissues or in the peripheral circulation, mediate their effects on target cells by binding to cell surface receptors and initiating a signal transduction process that leads to modulation of gene expression in the nuclear compartment. The cytokine receptors share structural similarities with each other as well as with growth factor receptors. Among the differences, cytokine receptor family members lack intrinsic tyrosine kinase activity and are referred to as non-tyrosine kinase receptors (NTK receptors), whereas the growth factor receptors possess intrinsic tyrosine kinase activity (tyrosine kinase receptors or TK receptors). The cytokine or NTK class of receptors recruit and activate members of the Janus kinase (JAK) family of nonreceptor cytoplasmic tyrosine kinases for mediation of events downstream of the plasma membrane, including activation of the signal transducer and activator of transcription (STAT) family of transcription factors by tyrosine phosphorylation. This receptor–JAK–STAT pathway is a common and rapid signaling pathway used by cytokines to regulate diverse cellular functions, including cell growth, differentiation, division, and apoptosis. Binding of a cytokine to its receptor is believed to induce a dimerization or oligomerization of the receptor chains and subsequent activation of one or more members of the JAK protein family (four members designated JAK1, JAK2, JAK3, and Tyk2) by tyrosine phosphorylation in trans. The activated JAKs catalyze the tyrosine phosphorylation of tyrosine motifs on the cytoplasmic tails of the receptors. Latent STATs get recruited to these tyrosine phosphorylated docking motifs through their SH2 domains. These recruited STATs are then subjected to activation by tyrosine phosphorylation by JAK family members. Tyrosine phosphorylated STATs then translocate to the nucleus and modulate gene transcription. Recent evidence suggests that components of the JAK–STAT pathway, including JAKs, STATs, the cytokine receptor chains, and other proteins, exist in preformed complexes within detergent-resistant “raft” microdomains at the levels of the plasma membrane. It may be speculated that these raft or caveolar microdomains are the gatekeepers for integration of combinatorial effects of multiple growth factors and cytokines acting simultaneously. The search for mechanisms that regulate the JAK–STAT pathway has led to the discovery of the suppressor of cytokine signaling (SOCS) family of proteins that mediate attenuation of JAK activity.