Description

Vascular endothelial growth factor signaling pathway (VEGF) regulates vasculogenesis, angiogenesis, lymphanogiogenesis and vascular permeability as well as the migration of monocytes and macrophages and the recruitment of haematopoietic cells. Several VEGFs (five in mammals) bind to one or more of the three VEGF receptor tyrosine kinases (RTK) to accomplish these important vascular functions. By far, the best characterized receptor and the focus of this synopsis and diagram is Kdr also known as Vegfr-2 (other ligands, receptors and associated processes are shown but not described). Vegfa - the ligand for Kdr, is a secreted, dimeric glycoprotein present as several alternatively spliced isoforms. According to the model, Vegfa binding to the second and third extracellular Ig-like domain of the Kdr monomer leads to ligand binding by a second monomer; stabilization of the receptor dimer, proper positioning of the kinase domains  and finally, receptor autophosphorylation. Several tyrosine residues are present in the intracellular domain of Kdr; some have been shown to be critical for the recruitment of specific SH2 (Src homology 2) domain containing adapter and target proteins to trigger downstream signaling events. Binding to and phosphorylation of Plcg1 leads to increased activity of the enzyme and formation of the second messengers IP3 and DAG; DAG activates Prkcg or b1 which leads to activation of the RAF/MEK/ERK pathway. Shb (note a different color meaning the gene is not present in all three species) appears to be involved in the activation of PI3K triggering the PI3K-Akt signaling pathway; both Shb (possibly via Ptk2) and Sh2d2a may relay the Kdr signal to cytoskeletal reorganization and migration. Activated Kdr has been implicated in actin remodeling via the p38 MAPK signaling pathway downstream of Cdc42; Nck1 may provide the relay, possibly through its association with Fyn of the Src family kinase. The interaction of ligands and receptors with Nrp1 or 2 co-receptors and with other molecules such as heparin sulfate, cadherins and integrins further shape VEGF signaling. Crosstalk with other signaling pathways such as Notch or TGF has been reported, but a more detailed understanding of the underlying molecular mechanisms is still lacking. Given the prominent role Kdr mediated signaling plays in the angiogenic programme and the importance of angiogenesis for tumor development, inhibition of the pathway has emerged as an attractive prospect for the development of anti-cancer therapeutics. To see the ontology report for annotations, GViewer and download, click here

 Abbreviations

VEGF – vascular endothelial growth factor

Kdr – kinase insert domain protein receptor (also known as Vegfr-2)

Vegfa – vascular endothelial growth factor A

Flt1 – FMS-like tyrosine kinase (also known as Vegfr-1)

Vegfb – vascular endothelial factor B

Pgf – placental growth factor

Flt4 – FMS-like tyrosine kinase 4 (also known as Vegfr-3)

Vegfc – vascular endothelial growth factor C

Figf – c-fos induced  growth factor (also known as ascular endothelial growth factor D)
Plcg1 - phospholipase C, gamma 1
Prkcg – protein kinase C, gamma
Prkcb1 – protein kinase C, beta 1
Shb – Src homology 2 domain containing adaptor protein B
Ptk2 – Ptk2 protein tyrosine kinase 2 (also known as Fak or focal adhesion kinase)
Sh2d2a – SH2 domain protein 2A (also known as VRAP or TSad)Nck1 – non-catalytic region of tyrosine kinase adaptor protein 1
Fyn – fyn proto-oncogene
Nrp1 – neuropilin 1

Nrp2 – neuropilin 2

 

References

PMID:17658244, 16633338, 16336962, 16465447, 16835467, 17503412, 18348190, 18369162, 17344076