The PTK-STAT signaling pathway has essential roles in T-cell activation in response to antigen stimulation.

Abstract

A variety of polypeptide ligands, including growth factors, cytokines, antigens, and cell matrix proteins, transduce signals through activation of protein tyrosine kinases (PTKs) (van der Geer et al. 1994). PTK activationresults in further tyrosine phosphorylation of downstreamsignaling proteins that have functions in control of cellmetabolism, proliferation, differentiation, and otherphenotypes. A direct signaling pathway through tyrosinephosphorylation of STAT (signal transducer and activator of transcription) proteins was revealed first in theinterferon system (Darnell et al. 1994; Fu 1995).Interferon-α (IFN-α) activates a transcription factor complex, termed ISGF3, which preexists in a latent form inthe cytoplasm, and translocates to the nucleus upon stimulation (Dale et al. 1989; Levy et al. 1989). The ISGF3complex was purified, and its components (p113, p91,p84, and p48) were identified from IFN-α-treated HeLacells (Fu et al. 1990). Molecular cloning of two ISGF3components, p91 and p113, led to the discovery of theSTAT protein family (Fu et al. 1992; Schindler et al.1992b). STAT proteins contain a Src homology region 2(SH2) domain and can bind directly to tyrosine-phosphorylated membrane receptor complexes (Fu 1992; Fu andZhang 1993; Greenlund et al. 1994; Stahl et al. 1995).STAT proteins are then activated by tyrosine phosphorylation (Fu 1992; Schindler et al. 1992a), which leads todimer formation through intermolecular interactions between the SH2 domains and phosphotyrosine residues(Hou et al. 1994; Shuai et al. 1994). The STAT dimertranslocates to the nucleus and regulates expression of aspecific set of genes. Today, seven STAT family members are known in mammalian cells, which have essentialroles in mediating gene induction in response to manykinds of extracellular signals (Darnell 1997)...