Fig. 6

LRG1 signalling pathways. Simplified schematic representation of generic signalling pathways known, or speculated, to be modulated by LRG1 in a cell-specific manner. LRG1 likely modifies cell behaviour both directly, by altering the cell transcriptome, and indirectly by interfering with intermediate steps of the signalling cascades. LRG1 has been mainly described as a modifier of the TGFβ canonical pathway. While promoting pathogenic angiogenesis in endothelial cells through the ALK1-Smad1/5/8 pathway [4, 23], LRG1 may also modulate the ALK5-Smad2/3 arm to favour the formation of myofibroblasts [16, 68] and Th₁₇ lymphocytes [27], thus sustaining fibrosis and inflammation, as well as glioma cell migration [194]. TGFβ non-canonical signalling is also likely to mediate some of the LRG1-driven biological functions including neutrophil activation and wound healing via AKT [56, 64], as well as the modulation of stem/cancer cell phenotype via ROCK1 [39] and p38/MAPK [31, 87]. Activation of the TGFβ-related transcription factors HIF-1α [197] and RUNX1 [50] has also been associated with LRG1 pro-oncogenic functions, although the specific upstream pathways subject to LRG1 modification in this context remain to be formally clarified. Additional transduction factors involved in LRG1 signalling include (i) EGFR which promotes pancreatic cancer cell malignancy through p38/MAPK [49], dissemination of melanoma cells [90] and cornea repair through STAT3 [64]; (ii) the IL-6/STAT3 axis which modulates neutrophil chemotaxis [57]; (iii) Wnt/βcatenin which, in the heart, inhibit fibroblast proliferation and migration [37]. Further investigations are needed to address whether LRG1 modulates the activity of other receptor-mediated signalling pathways including BMPs, and whether other receptors may also be directly or indirectly affected by LRG1. BMP bone morphogenic protein, EC endothelial cell, FBS fibroblast, EMT epithelial-mesenchymal transition, FZD Frizzled, TF transcription factor, NET neutrophil extracellular trap