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. 2021 Jul 12;9:696542. doi: 10.3389/fcell.2021.696542

FIGURE 3.

FIGURE 3

Cross-talks among signaling pathways. (A) PI3K/Akt signaling pathway: PI3K is activated to transform PIP2 into PIP3, which promotes the accumulation of Akt with the assistance of PDK1 at the plasma membrane. Activated Akt then translocates into nucleus to exert its biological function. (B) JAK/STAT signaling pathway: The signaling cascade of JAK/STAT signaling pathway including JAK activation, tyrosine phosphorylation, and STAT recruiting. Then, the STAT is transported to nucleus to regulate gene transcription. (C) TGF-β/Smad signaling pathway: Activated TGF-β binds to its receptors and thus phosphorylates Smad2 and Smad3. Smad2/3 then forms an oligomeric complex with Smad4, which translocates into the nucleus to regulate the transcription of target genes. (D) Wnt/β-catenin signaling pathway: The Wnt binds to the frizzled receptor, which works together with the LRP5 and LRP6 co-receptors to inhibit the ubiquitination of destruction complex. Therefore, the degradation activity of β-catenin is limited, causing the accumulation of β-catenin, which translocates from the cytoplasm to the nucleus to regulate the transcription. (E) Notch signaling pathway: Upon the combination of the receptor Notch, and the ligand JAG and DL, Notch transforms to the activated form NICD, which enters the nucleus to regulate the expression of downstream targets. (F) TGF-β directly activates PI3K and subsequently stimulates Akt production. (G) TGF-β can activate both JAK and STAT, and the activation of JAK subsequently stimulates the phosphorylation of STAT3. (H) The activation of the TGF-β/Smad pathway stimulates MAPK, while MAPK directly induces the phosphorylation of the linker of Smad3, thereby promoting the transcriptional activity of Smad. Extracellular MAPK activation can stimulate latent TGF-β in mesangial cells via TSP-1 or AP-1. (I) TGF-β pathway activates Wnt pathway by downregulating the level of Wnt antagonist DKK1. β-catenin can bind with Smad3, promoting the transcription of Smads. (J) TGF-β pathway upregulates the ligand of Notch, such as JAG, to transform Notch to NICD. NICD can interact directly with Smad3, which is enhanced by TGF-β administration. PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-biphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PDK1, 3-phosphoinositide-dependent protein kinase 1; JAK, Janus kinase; STAT, signal transducer and activator of transcription; LRP, low-density lipoprotein receptor-related proteins; NICD, notch intracellular domain; TSP-1, thrombospondin-1; AP-1, activator protein 1; DKK-1, Dickkopf-1.