Table 1. FGF2 binding partners and associated proteins.
| Associated Protein | Association | Level of Interaction | Cell Type | Pathway | Ref |
|---|---|---|---|---|---|
| FGFR(s) | FGF2 binds to extracellular domain of FGFRs which causes receptor dimerization and autophosphorylation of tyrosine kinase residues on cytoplasmic domain | Cell membrane | Endothelial cells, cancer cells, fibroblasts | FGFR | [12, 101] |
| HSPG | FGF2 binds with low affinity to heparan sulfate chains of HSPG. This interaction can activate intracellular signaling, promote FGF2 internalization, or by presenting FGF2 to FGFR in proper conformation. HSPG also act as reservoirs for FGF2 which protect them from degradation | Cell membrane | Cancer, endothelial cells | FGFR | [102–104] |
| αvβ3 integrin | FGF2 binds to αvβ3 integrin leads to assembly of focal adhesion plaques | Cell membrane | Endothelial cells | FAK | [105] |
| Gangliosides | Gangliosides bind FGF2 via Neu-Ac residues and acts as coreceptors | Cell membrane | Endothelial cells | FGFR | [106] |
| Free gangliosides | Exogenous gangliosides affect the angiogenic activity of FGF2. Exogenous gangliosides act as FGF2 antagonists when added to endothelial cell cultures | Soluble or associated with ECM | Cancer, endothelial cells | FGFR | [107] |
| Heparin | Short heparin chains bind FGF2, thus interfering with mitogenic signaling through activation of FGFR, relatively longer chains are expected to induce the adverse effect of potentiating the mitogenic signaling | Soluble or associated with ECM | Tumor Cells | FGFR | [108] |
| xcFGFR1 | A soluble form of extracellular domain of FGFR1 which binds to FGF2 which leads to suppression of FGF2/FGFR1 interaction | Soluble | Endothelial ECM | FGFR | [107] |
| TSP | TSP-1 and TSP-2 regulate angiogenesis through binding and sequestration of FGF2 | Soluble or associated with ECM | Cancer, endothelial cells | FGFR | [109, 110] |
| PTX3 | PTX3 prevents FGF2 binding to FGFRs on endothelial cells, leading to inhibition cell proliferation and motility. PTX3 suppressed neovascularization triggered by FGF2 in the chick embryo chorioallantoic membrane | Soluble or associated with ECM | Endothelial cells | FGFR | [111] |
| Fibrinogen/ fibrin | Binding of FGF2 to fibrinogen or fibrin provides protection of FGF2 from proteolytic degradation. Fibrinogen potentiates FGF2-stimulated proliferation of endothelial cells. Fibrinogen promotes growth of cancer cells through interaction with FGF2 | Soluble or associated with ECM | Endothelial cells, cancer cells | FGFR | [112, 113] |
| α2M | α2M induces FGF2 expression in embryonic stem cells | Nucleus | Embryonic stem cells | ERK1/2, PI3K, | [114] |
| PDGF | FGF2 stimulates PDGFR-α and β expression in endothelial cells | Nucleus | Endothelial cells | Transcriptional | [115] |
| PF4 | PF4 inhibits FGF2-induced proliferation of endothelial cells. PF-4 binds to FGF2 and inhibits FGF2 dimerization, binding to FGFRs, and internalization | Soluble or associated with ECM | Endothelial cells | ERK | [116, 117] |
| uPA | FGF2 upregulates uPA receptor and stimulates uPA production by endothelial cells | Nucleus | Endothelial cells | Transcriptional | [118] |
| CXCL13 | CXCL13 chemokine displaces FGF2 binding to endothelial cells, inhibits FGF2 homodimerization, and induces the formation of CXCL13-FGF2 heterodimers | Soluble or associated with ECM | Endothelial cells | FGFR | [119] |
| IL-6 | FGF2 induces IL-6 release in human pancreatic periacinar myofibroblasts. Overexpression of FGF2 (24-kDa isoform) upregulates IL-6 transcription in NIH-3T3 cells. FGF2 is downstream effector of IL-6-induced angiogenic activity in cancer cells | Soluble or associated with ECM/Nucleus | Fibroblasts, cancer cells | IL-6, ERK1/2 and p38 MAP kinases | [120–122] |
| E-cadherin | FGF2 downregulates E-cadherin expression through the activation of PI3K/Akt/mTOR and MAPK signaling, and upregulates Slug and ZEB1 in human ovarian cancer cells | Nucleus | Cancer, endothelial cells | PI3K/Akt and ERK | [123] |
| Bcl-2 | FGF2 downregulates Bcl-2 and promotes apoptosis in human breast cancer cells | Nucleus | Cancer cells | Transcriptional | [124] |
| Aquaporin3 | Aquaporin3 is required for FGF2-induced cell migration in human breast cancer cells | Soluble or associated with ECM | Cancer cells | Trans-epithelial fluid transport | [125] |
| Translokin | Translokin interacts specifically with LMW FGF2. Inhibiting Translokin expression by RNA interference reduces the translocation of FGF2 | Soluble or associated with ECM | Fibroblasts | FGF2 trafficking | [126] |
| Thrombin | Thrombin cleaves HMW FGF2 into a LMW FGF2-like form that stimulates endothelial cell migration and proliferation | Soluble or associated with ECM | Endothelial, cancer cells | Endothelial cell migration | [127] |
| FGF-binding protein | FGF-BP 1 binds FGF2 and enhances FGF2-dependent proliferation of NIH-3T3 fibroblasts and FGF2-induced extracellular signal-regulated kinase 2 phosphorylation | Soluble or associated with ECM | Squamous, epithelial cells, fibroblasts | FGFR | [128] |
α2M: α2-macroglobulin; ECM: extracellular matrix; FAK: focal adhesion kinase; HSPG: heparan sulfate proteoglycan; IL-6: interleukin-6; PDGF: platelet-derived growth factor; PF4: platelet factor 4; PTX3: p; TSP: thrombospondin-2; uPA: urokinase-type plasminogen activator