scholarly journals Tofacitinib Represses the Janus Kinase-Signal Transducer and Activators of Transcription Signalling Pathway in Keratinocytes

2018 ◽  
Vol 98 (8) ◽  
pp. 772-775 ◽  
Author(s):  
A Srivastava ◽  
M Ståhle ◽  
A Pivarcsi ◽  
E Sonkoly
Keyword(s):  
Signalling Pathway ◽  
Janus Kinase ◽  
Signal Transducer

scholarly journals Novel role of STAT3 in microglia-dependent neuroinflammation after experimental subarachnoid haemorrhage

2021 ◽  
pp. svn-2021-001028
Author(s):  
Zhiyuan Vera Zheng ◽  
Junfan Chen ◽  
Hao Lyu ◽  
Sin Yu Erica Lam ◽  
Gang Lu ◽  
...  
Keyword(s):  
Subarachnoid Haemorrhage ◽  
Inflammatory Responses ◽  
Morphological Changes ◽  
Neuronal Loss ◽  
Signalling Pathway ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Experimental Subarachnoid Haemorrhage ◽  
Stat3 Signalling

Background and purposeSignal transducer and activator of transcription 3 (STAT3) may contribute to the proinflammation in the central nervous system diseases by modulating the microglial responses. Thus, this study was intended to investigate the effect of STAT3 on microglia-dependent neuroinflammation and functional outcome after experimental subarachnoid haemorrhage (SAH).MethodsThe SAH model was established by endovascular perforation in the mouse. Real-time PCR (RtPCR) and western blot were used to examine the dynamic STAT3 signalling pathway responses after SAH. To clarify the role of the STAT3 signalling pathway in the microglia-dependent neuroinflammation after SAH, the microglia-specific STAT3 knockout (KO) mice were generated by the Cre-LoxP system. The neurological functions were assessed by Catwalk and Morris water maze tests. Neuronal loss after SAH was determined by immunohistochemistry staining. Microglial polarisation status after STAT3 KO was then examined by RtPCR and immunofluorescence.ResultsThe STAT3 and Janus kinase-signal transducer 2 activated immediately with the upregulation and phosphorylation after SAH. Downstream factors and related mediators altered dynamically and accordingly. Microglial STAT3 deletion ameliorated the neurological impairment and alleviated the early neuronal loss after SAH. To investigate the underlying mechanism, we examined the microglial reaction after STAT3 KO. STAT3 deletion reversed the increase of microglia after SAH. Loss of STAT3 triggered the early morphological changes of microglia and primed microglia from M1 to M2 polarisation. Functionally, microglial STAT3 deletion suppressed the SAH-induced proinflammation and promoted the anti-inflammation in the early phase.ConclusionsSTAT3 is closely related to the microglial polarisation transition and modulation of microglia-dependent neuroinflammation. Microglial STAT3 deletion improved neurological function and neuronal survival probably through promoting M2 polarisation and anti-inflammatory responses after SAH. STAT3 may serve as a promising therapeutic target to alleviate early brain injury after SAH.

scholarly journals STAT genes display differential evolutionary rates that correlate with their roles in the endocrine and immune system

2011 ◽  
Vol 209 (2) ◽  
pp. 175-184 ◽  
Author(s):  
Marnix Gorissen ◽  
Erik de Vrieze ◽  
Gert Flik ◽  
Mark O Huising
Keyword(s):  
Immune System ◽  
Phylogenetic Analyses ◽  
Evolutionary Conservation ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Primary Sequence ◽  
Immune Systems ◽  
Stat Proteins ◽  
Evolutionary Forces ◽  
Endocrine Hormones

We identified orthologues of all mammalian Janus kinase (JAK) and signal transducer and activator of transcription (STAT) genes in teleostean fishes, indicating that these protein families were already largely complete before the teleost tetrapod split, 450 million years ago. In mammals, the STAT repertoire consists of seven genes (STAT1, -2, -3, -4, -5a, -5b, and -6). Our phylogenetic analyses show that STAT proteins that are recruited downstream of endocrine hormones (STAT3 and STAT5a and -5b) show a markedly higher primary sequence conservation compared with STATs that convey immune signals (STAT1-2, STAT4, and STAT6). A similar dichotomy in evolutionary conservation is observed for the JAK family of protein kinases, which activate STATs. The ligands to activate the JAK/STAT-signalling pathway include hormones and cytokines such as GH, prolactin, interleukin 6 (IL6) and IL12. In this paper, we examine the evolutionary forces that have acted on JAK/STAT signalling in the endocrine and immune systems and discuss the reasons why the JAK/STAT cascade that conveys classical immune signals has diverged much faster compared with endocrine JAK/STAT paralogues.

A common epitope is shared by activated signal transducer and activator of transcription-5 (STAT5) and the phosphorylated erythropoietin receptor: implications for the docking model of STAT activation

Blood ◽  
2001 ◽  
Vol 97 (8) ◽  
pp. 2230-2237 ◽  
Author(s):  
Dwayne L. Barber ◽  
Bryan K. Beattie ◽  
Jacqueline M. Mason ◽  
Melody H.-H. Nguyen ◽  
Monique Yoakim ◽  
...  
Keyword(s):  
Structural Features ◽  
Sh2 Domain ◽  
Erythropoietin Receptor ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Specific Antibodies ◽  
Docking Model ◽  
Receptor Interactions ◽  
Cytokine Stimulation ◽  
Carboxy Terminal

Abstract Erythropoietin (EPO) specifically activates the Janus kinase JAK2 and the transcription factor signal transducer and activator of transcription-5 (STAT5). All members of the STAT family are tyrosine phosphorylated in response to cytokine stimulation at a conserved carboxy-terminal tyrosine, Y694, in the case of STAT5. To determine structural features important for STAT signaling, we generated an activation-specific STAT5 antibody using a phosphopeptide containing amino acids 687 to 698 of STAT5 as antigen. This antibody specifically recognizes tyrosine- phosphorylated STAT5 but not nonphosphorylated STAT5. In immunoprecipitation reactions from cell lines and primary erythroblasts, 2 distinct polyclonal activation-specific STAT5 antibodies selectively immunoprecipitate the tyrosine phosphorylated EPO receptor (EPO-R) in addition to STAT5 under native and denaturing conditions. We propose that the activation-specific STAT5 antibody recognizes the 2 substrates to which the STAT5 SH2 domain interacts, namely, the tyrosine- phosphorylated EPO-R and STAT5 itself. Several studies have implicated EPO-R Y343, Y401, Y431, and Y479 in the recruitment of STAT5. Using a series of EPO-R tyrosine mutants expressed in Ba/F3 cells, we have shown that the activation-specific STAT5 antibody immunoprecipitates an EPO-R containing only 2 tyrosines at positions 343 and 401, confirming the importance of these tyrosines in STAT5 recruitment. These data uncover a novel aspect of STAT SH2 domain recognition and demonstrate the utility of activation-specific antibodies for examining the specificity of STAT–cytokine receptor interactions.

Sign in / Sign up

Export Citation Format

Share Document