Abstract
Signal transducer and activator of transcription (STAT) plays an essential role in the inflammatory reaction and immune response of numerous renal diseases. STATs can transmit the signals of cytokines, chemokines, and growth factors from the cell membrane to the nucleus. In the canonical STAT signaling pathways, upon binding with their cognate receptors, cytokines lead to a caspase of Janus kinases (JAKs) and STATs tyrosine phosphorylation and activation. Besides receptor-associated tyrosine kinases JAKs, receptors with intrinsic tyrosine kinase activities, G-protein coupled receptors, and non-receptor tyrosine kinases can also activate STATs through tyrosine phosphorylation or, alternatively, other post-translational modifications. Activated STATs translocate into the nucleus and mediate the transcription of specific genes, thus mediating the progression of various renal diseases. Non-canonical STAT pathways consist of preassembled receptor complexes, preformed STAT dimers, unphosphorylated STATs (U-STATs), and non-canonical functions including mitochondria modulation, microtubule regulation and heterochromatin stabilization. Most studies targeting STAT signaling pathways have focused on canonical pathways, but research extending into non-canonical STAT pathways would provide novel strategies for treating renal diseases. In this review, we will introduce both canonical and non-canonical STAT pathways and their roles in a variety of renal diseases.
Highlights
Signal transducer and activator of transcription (STAT) is a family of latent transcription factors involved in the signaling of diverse ligands such as cytokines, chemokines, and growth factors
The STAT family includes seven mammalian STATs: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6, which share several similar domains: N-terminal homotypic dimerization domains involved in dimerization/tetramerization; coiled-coil domains involved in interaction with other proteins; DNA binding domain (DBD); linker domain; SRC homology 2 (SH2) domain; phosphor–tyrosine residue; transactivation domain [6]
While, during the progression of Autosomal dominant polycystic kidney disease (ADPKD), the cleaved PC1 tail could co-activate STAT1 that had been activated by IFN, STAT3 that had been activated by IL-6, EGF, HGF signaling, STAT6 that had been activated by IL4, IL-13 signaling to promote renal cyst growth and fibrosis [108]
Summary
Signal transducer and activator of transcription (STAT) is a family of latent transcription factors involved in the signaling of diverse ligands such as cytokines, chemokines, and growth factors. The signals can be transmitted from the cell membrane to the nucleus by initiating caspase of tyrosine kinases and STATs phosphorylation and activation, binding to response elements of DNA and inducing the transcription of target genes [1]. The STAT signaling pathways enable cells to rapidly initiate a transcriptional response to external stimulation. IL-6 family members: IL-6, IL-11, OSM, LIF, CLCF1, CNTF and erythropoietin, et al. Growth factors: EGF and HGF, et al. Cell mitogenesis; Oncogenesis; Cell proliferation; Th17 differentiation [1,7]. INF, interferon; IL, interleukin; OSM, oncostatin M; LIF, leukemia inhibitory factor; CLCF, cardiotrophin-like cytokine factor; CNTF, ciliary neurotrophic factor; EGF, epidermal growth factor; HGF, hepatocyte growth factor; Th, T helper lymphocytes; GM-CSF, granulocytemacrophage colony-stimulating factor; Treg, regulatory T lymphocyte. Some studies have shown that non-canonical pathways play an important role in the development of renal diseases. In this review we will illustrate both the canonical and non-canonical STAT pathways in order to provide new insights to develop effective interventions for renal diseases
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