Jak/STAT Signaling Pathway Intracellular Regulation

Overview of Jak/STAT Signaling Pathway: Intracellular Regulation

The Jak/STAT pathway can be activated by a large number of cytokines, including type I/II Interferons and members of the IL-6, IL-10, IL-12, Common gamma Chain, and Common beta Chain families, as well as numerous growth factors. Binding of the cytokine or growth factor to its receptor typically initiates oligomerization of the receptor chains allowing the associated Janus Kinases (Jaks) to activate each other by reciprocal tyrosine phosphorylation. The activated Jak proteins subsequently phosphorylate the receptor, creating binding sites for Signal Transducers and Activators of Transcription (STATs). Once bound to the receptor, STAT transcription factors are phosphorylated by Jaks or other kinases. Activated STAT proteins dissociate from the receptor and dimerize. STAT dimers translocate to the nucleus where they complex with other nuclear proteins and regulate the expression of target genes.

Signaling through the Jak/STAT pathway is tightly controlled by a number of distinct mechanisms. Key regulators of this pathway include Suppressors of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIASs), and protein tyrosine phosphatases (PTPs). The SOCS proteins are the primary regulators of the Jak/STAT pathway. This family of Src homology 2 (SH2) domain-containing proteins is composed of SOCS-1, -2, -3, -4, -5, -6, -7, and Cytokine-inducible SH2-containing Protein 1 (CIS-1), also known as CISH and SOCS. SOCS proteins form a classic negative-feedback loop of cytokine signaling. They are typically expressed at low levels and become rapidly induced following cytokine activation of the Jak/STAT pathway. SOCS proteins can inhibit Jak/STAT signaling through several mechanisms. These proteins bind via their SH2 domain to phosphorylated tyrosine residues on receptors thereby blocking STAT binding and activation. SOCS can also inhibit Jak activity. The N-terminal kinase inhibitory region (KIR) of SOCS proteins associated with phosphorylated Jaks and receptors act as a pseudo-substrate for the Jak kinases. SOCS also target multiple components of the Jak/STAT pathway for proteasomal degradation. SOCS proteins contain a C-terminal SOCS box that associates with Elongins B and C, Cullin 5 (Cul5), and the RING finger protein Rbx-1 to form a Ubiquitin ligase (E3) complex. Rbx-1 subsequently recruits a Ubiquitin-conjugating (E2) enzyme, and the multi-protein complex tags targeted proteins with polyubiquitin chains, marking them for degradation by the proteasome. SOCS have been shown to target activated Jaks and receptors for degradation by the proteasome. Interestingly, SOCS will also regulate its own activity by directing phosphorylated SOCS proteins to the proteasome.

The PIAS family of regulators is composed of PIAS1, PIAS2, PIAS3, and PIAS4. PIAS2 and PIAS4 are also known as PIASx and PIASy, respectively. PIAS proteins are constitutively expressed and interact with activated STAT dimers to inhibit STAT-mediated transcription. PIAS1 and PIAS3 prevent STAT dimers from binding to DNA. Alternatively, PIAS2 and PIAS4 repress STAT-mediated gene expression without affecting STAT DNA binding activity. They recruit transcriptional repressors, such as histone deacetylases (HDACs), to inhibit the transcriptional activities of STAT proteins. PIAS proteins can also function as RING-type SUMO ligases to mediate SUMOylation of STAT dimers. Their zinc-binding RING-finger domain associates with the E2 conjugase Ubiquitin-conjugating Enzyme E2I (UBE2I), also known as Ubiquitin-conjugating Enzyme 9 (Ubc9), to facilitate the covalent attachment of SUMO to STAT dimers. It is thought that SUMOylation modulates the DNA-binding properties of STAT proteins.

Jak/STAT signaling is also regulated by numerous constitutively expressed PTPs that dephosphorylate important tyrosine residues on multiple components of the pathway thereby attenuating Jak/STAT signaling. One main PTP family is the SH2 domain-containing phosphatases comprised of SHP-1 and SHP-2. SHP proteins bind to phosphorylated receptors, Jak proteins, and STATs via their SH2 domain to facilitate dephosphorylation. Additionally, nuclear SHP proteins dephosphorylate STAT dimers, inhibiting their transcriptional activities and possibly facilitating their nuclear export. Conversely, SHP-2 has been shown to also promote cytokine signaling. SHP-2 dephosphorylates tyrosine residues on Jak proteins that are critical for SOCS-mediated inhibition of Jak activity. Several other PTPs, including Protein Tyrosine Phosphatase 1B (PTP1B), T cell Protein Tyrosine Phosphatase (TC-PTP), and Protein Tyrosine Phosphatase Non-receptor Type 13 (PTPN13), dephosphorylate and attenuate the activity of Jak and STAT proteins. Additionally, CD45, a receptor PTP, directly binds to and dephosphorylates all Jak molecules.

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