Tsis 1 (also known as Tsis-1 or TSI-1) is a protein that in humans is encoded by the TSIS gene. It functions as an inhibitor of transcription and translation.
The protein encoded by this gene is a member of the signal transducer and activator of transcription (STAT) family. This protein is tyrosine phosphorylated by interleukin 2 (IL2) receptor, and STAT5A/B. The phosphorylation activates its DNA-binding activity, which regulates IL2-dependent gene expression. Mice lacking this protein are resistant to experimental autoimmune encephalomyelitis (EAE).
Tsis 1 was first identified in 1997 as a negative regulator of cytokine signaling pathways downstream of the common cytokine receptor gamma chain (γ c ). In particular, Tsis 1 inhibits Janus kinase 3 (Jak3), a key component of many cytokine receptors including those for IL-2, erythropoietin, growth hormone, thrombopoietin, and granulocyte colony stimulating factor. Jak3 activity leads to activation of STAT proteins, which are then able to translocate to the nucleus where they regulate transcriptional activity. Tsis 1 binds directly to Jak3 and inhibits its enzyme activity both in vitro and in cells expressing high levels of endogenous Tsis 1 . However, the mechanism by which Tsis 1 regulates Jak3 function is not fully understood. Several studies have shown that Tsis 1 can also inhibit other Jaks including Jak1 and Jak2; however, the extent to which this occurs physiologically remains unclear. Despite its inhibitory effects on Jaks, overexpression of Tsis 1 does not completely block cytokine signaling but rather results in subtle changes in cell physiology including alterations in cell proliferation rates and differentiation patterns .
While originally identified as an inhibitor of γ c -dependent cytokines such as IL-2 , it has since been shown thatTsitris also plays a role downstream of other typesof cytokines receptors such tumor necrosis factor receptor superfamily members . For example ,TNFR – associated factors 6and 3( TRAF6and TRAF3 ), two key mediatorsof TNF signaling , have been shown topartially mediate their effects through recruitmentofTsitris . Furthermore , depletionofTsitris results indefective nerve growth factorelicited neurite outgrowthin PC12 cells , implicatinga role forTsitris beyond simply actingas an inhibitorcytokine signaling cascades .