Figure 2
From: Growth factor regulation of proliferation and survival of multipotential stromal cells
Growth factor signaling pathways mediating proliferation in multipotential stromal cells. Binding of fibroblast growth factor (FGF) to fibroblast growth factor receptor (FGFR), binding of epidermal growth factor (EGF) and heparin-binding (HB)-EGF to epidermal growth factor receptor (EGFR) and binding of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) to platelet-derived growth factor receptor (PDGFR) causes phosphorylation of the respective receptors, causes recruitment of the adaptor protein Grb2 and the nucleotide exchange factor SOS, which causes activation of downstream pathways, primarily phosphoinositide-3 kinase (PI3K)-Akt/protein kinase B (PKB) and the mitogen-activated protein kinase (MAPK) Erk. Phosphorylated Erk either enters the nucleus and activates transcription of cellular proliferation genes like c-myc, or activates downstream receptors like Rsk that then activates proliferation genes. Akt similarly prevents the expression of proteins like Myt1 and Wee1, which are involved in inhibiting proliferation. Bone morphogenetic protein (BMP)-2 activates proliferation via the MAPK Erk pathway, unlike BMP-3 that activates Smad2 and Smad3 via Activin signaling. TGFβ3 is the most potent transforming growth factor beta (TGFβ) mitogen causing proliferation via activation of Smad2, Smad3 and Smad4. Binding of Wnt3a to the Frizzled receptor causes activation of the protein Dishevelled and inactivation of the Axin-APC-Gsk3 complex, which leads to a nuclear influx of β-catenin, activating the cell cycle proteins cyclin D1 and c-myc. TGFβ also causes an influx of β-catenin in a Smad3-dependent manner. Binding of hepatocyte growth factor (HGF) to c-Met under low doses causes activation of Erk and Akt, but under higher doses it inhibits proliferation by activating the p38 MAPK pathway and causing the expression of cell cycle progression inhibitors p21Waf1 and p27Kip. APC, adenomatous polyposis coli protein; Gsk3, glycogen synthase kinase 3; RSK, ribosomal S6 kinase; Smad. Sma and Mad related proteins.