Intracellular signal transduction pathways are essential for connecting extracellular cytokine stimulations to appropriate cellular responses, such as proliferation, differentiation, and apoptosis. One of the most important pathways activated by cytokines is the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, which was initially discovered in the studies on gene induction by interferon (IFN) (1
). It is now clear that protein phosphorylation and dephosphorylation play a central role in controlling the activity of the JAK/STAT pathway. The majority of phosphorylation and dephosphorylation occur at tyrosine residues of the component proteins, which are carried out by protein tyrosine kinases and protein tyrosine phosphatases (PTP), respectively (2
). This short article summarizes latest insights into how PTPs, including SHP2, SHP1, CD45, PTP1B, T-cell PTP (TC-PTP), PTPRT, and PTPBL, regulate the JAK/STAT pathway.
In the current model of the JAK/STAT signaling pathway, the engagement between a cytokine and its cell surface receptor results in receptor oligomerization and subsequent activation of receptor-associated JAK tyrosine kinases. Activated JAKs phosphorylate specific tyrosine resides in the cytoplasmic domain of the receptor which in turn serves as the docking sites for cytoplasmic transcription factors known as STATs. STATs are therefore recruited to the phosphorylated receptor and subsequently phosphorylated by JAKs. The phosphorylated STATs then dimerize, leave the receptor, and translocate to the nucleus where they activate gene transcription (5
). In mammalian cells, four JAK members (JAK1, JAK2, JAK3, and TYK2) have been identified. Each JAK contains a conserved kinase domain and a catalytically-inactive domain at the carboxyl (C-) terminus which might regulate the activity of the kinase domain. There are seven members (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6) in the mammalian STAT family. Each of them contains a DNA-binding domain, a transactivation domain located at the C-terminus (7
), and a SRC homology 2 (SH2) domain. The SH2 domain is required for STAT activation and dimerization (9
) while the amino (N-) terminal region of STAT is involved in the formation of STAT tetramers (11
) and tyrosine dephosphorylation (12
). Genetic knockout studies have revealed various but specific functions of JAKs and STATs. One who is interested in details about the structures and functions of JAKs and STATs could look at the reviews (2
). The following sections of this review will discuss how PTPs regulate JAK/STAT signaling with a focus on the SHP2 phosphatase, since the role of SHP2 in this context is more complicated than other PTPs.