Figure 3

Growth factor signaling pathways mediating survival in multipotential stromal cells. Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) bind PDGFR, and hepatocyte growth factor (HGF) binds c-Met, which causes phosphoinositide-3 kinase (PI3K) to be activated, converting PIP2 to PIP3 and activating Akt/protein kinase B (PKB). This leads to the inhibition of the Fork head family of transcription factors Foxo1, Foxo3 and Foxo4, and also causes inhibition of pro-death proteins Bim, Bad and Caspase9. At the same time there is activation of pro-survival proteins XIAP, Bcl2 and Bcl-xl. In addition, Akt activation causes activation of eNOS and HSP90, causing nitric oxide synthesis and angiogenesis that promotes survival. Binding of epidermal growth factor (EGF) to epidermal growth factor receptor (EGFR), in addition to activating Akt, brings together the guanine nucleotide exchange factor SOS and the small adapter protein Grb2, which activates the mitogen-activated protein kinase (MAPK) pathway: Ras-Raf-Mek1/2-Erk1/2. Activation of Erk leads to the expression of pro-survival proteins like NF-kB, Bcl2 and Bcl-xL. EGF binding to EGFR also causes PLCg to cleave PIP2 to IP3 and DAG, which activates protein kinase C (PKC). PKC can activate Raf and further cause downstream Erk activation. All these activated receptors, however, are quickly internalized by clathrin machinery or by alternate internalization mechanisms into the endosome where they continue to signal. The figure shows internalization of the EGF-EGFR complex continuing to signal in the cytosol, but once inside the lysosome, the receptor along with the ligand completely degrades and the survival signal is lost. Both the Akt and Erk signals generated therefore are acute and transient. Tethering of growth factors near the membrane, as in the case of EGF (tEGF), however, causes a more sustained signaling of Erk and Akt since the receptor-ligand complex signals for longer from the cell membrane, leading to multipotential stromal cell (MSC) survival for a more prolonged time period. Bcl2, B-cell lymphoma 2; DAG, diacylglycerol; Erk, extracellular signal related kinase; eNOS, endothelial nitric oxide synthase; HSP90, heat shock protein 90, IP3, inositol triphosphate; NF, nuclear factor; PDGFR, platelet-derived growth factor receptor; PLCg, phospholipase C gamma; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphotidylinositol-3,4,5-trisphosphate; XIAP, X-linked inhibitor of apoptosis protein.