3.1.4 Negative regulation of JAK-STAT pathway
In addition, there are three regulators and one activator identified in the JAK/STAT pathway: protein tyrosine phosphatases (PTPs), protein inhibitor of activated STAT (PIAS), suppressor of cytokine signaling (SOCS), and signal transducing adaptor molecule (STAM).
SHP-1, one of the PTPs, contains two SHP-2 domains, a catalytic PTP domain, a
divergent C-terminal region. SHP-2 domains bind to either the phosphorylated JAKs or other receptors to dephosphorylation these activated molecules(Bousquet, Susini & Melmed, 1999). Furthermore, other PTPs like PTP1B, CD45 and SHP2 are also reported roll in the JAK/STAT pathway(Irie-Sasaki et al., 2001; Xu & Qu, 2008; Yamada, Shiono, Joo & Yoshimura, 2003).
PIAS protein is another negatively regulator of the JAK/STAT pathway. It has five family members: PIAS1, PIAS3, PIASxα, PIASxβ, and PIASγ, each containing a putative Zn binding finger(Rawlings, Rosler & Harrison, 2004). It is an important transcriptional co-regulator of JAK-STAT. PIAS1binding to STAT1 inhibited its activity(Liao, Fu & Shuai, 2000; Liu et al., 1998). After IL-6 stimulation, PIAS3 was specific for the inhibition of STAT3-mediated gene expression(Borghouts, Tittmann, Delis, Kirchenbauer, Brill & Groner, 2010; Chung et al., 1997). PIAS was found also inhibit STAT1 associated gene expression not by affecting STAT1’s DNA binding activity(Liu, Gross, Ten & Shuai, 2001; Tahk, Liu, Chernishof, Wong, Wu & Shuai, 2007). PIAS1 is also ubiquitinated by a ubiquitin E3 ligase, HECTD2. HECTD2 polymorphism, HECTD2(A19P), prevented HECTD2/PIAS1 nuclear interaction, thus prevented PIAS1 degradation and protected toward acute respiratory distress syndrome (ARDS)(Coon et al., 2015).
SOCS was found several years ago as a family protein of JAK inhibitors and protected against lipopolysaccharide-induced acute lung injury(Severgnini et al., 2005a). The SOCS contain eight members: CIS and SOCS1-SOCS7, each with a central SH2 domain and an ~40 amino acid C-terminal region referred to as the SOCS box(Heinrich, Behrmann, Haan, Hermanns, Muller-Newen & Schaper, 2003). SOCS proteins are thought to bind to STAT5 and inhibit the activity of the receptor or JAK. CIS complete with STAT5 so modulate JAK2/STAT5 pathway(Cooney, 2002; Matsumoto et al., 1997; Yoshimura, 1998a; Yoshimura, 1998b). SOCS1 and SOCS3 are related in inhibition of IL-6-type cytokine signaling by inhibiting phosphorylation of gp130,STAT,JAK(Endo et al., 1997): SOCS1 bind to the activation loop of JAKs by its SH2 domain(Sasaki et al., 1999); nevertheless, SOCS3 may bind to the phosphoserine motif 759 of JAK2 and also bind to activation loop of JAK2 via its SH2 domain(Nicholson et al., 2000; Schmitz, Weissenbach, Haan, Heinrich & Schaper, 2000). And SOCS1 probably block JAK activity more efficient than SOCS3(Heinrich, Behrmann, Haan, Hermanns, Muller-Newen & Schaper, 2003).
The STAM proteins associated with JAKs are phosphorylated in response to cytokines, and serve to increase signaling(Pandey et al., 2000). So far, four members of the STAM family have been identified in human (STAM1, STAM2A, STAM2B, and EAST). All STAMs have a 140 amino acid VHS (present in Vps-27, Hrs, and STAM) domain in their N terminus, a central SH3 domain, and an ITAM motif (except STAM2B) in their C terminus.