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• Postreceptor signaling

Postreceptor signaling in the VEGF pathway

This image, adapted from a 2005 Journal of Clinical Oncology paper by Rini et al, is a simplified representation of the downstream cellular effects of the dimerization and activation of the VEGF/VEGFR-2 complex. The ensuing signaling cascade includes the PI3K/Akt pathway, which leads to endothelial cell survival; the p38MAPK pathway, which promotes endothelial cell migration; and the Raf pathway, which induces endothelial cell proliferation. All of these effects promote tumor angiogenesis.¹

Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043. Reprinted with permission from the American Society of Clinical Oncology.

Postreceptor signaling

Activation of vascular endothelial growth factor (VEGF) receptors (VEGFRs) can stimulate the expression of factors important for angiogenesis, including anti-apoptotic proteins, cell adhesion molecules, VEGFR-1, and matrix metalloproteinases (MMPs). A large body of evidence suggests that VEGFR-2 is the most important of the VEGF receptors with regard to angiogenesis, with postreceptor signaling pathways that promote endothelial cell division, permeability, and survival. However, there seems to be a great deal of cross-talk in the signaling pathways—still only partially understood—that ultimately translates VEGF receptor binding into angiogenesis.^2-6

"Extracellular signals modify intracellular processes through cognate receptors that elicit a cascade of events. However, a linear view of signal transduction falls short of describing all effects. Instead, branching, feedback, integration, and networking are characteristics of most if not all signal transduction pathways. Signaling cross-talk refers to a situation where one signal affects the output of another, seemingly distinct, signal transduction pathway."— Picard,

Pure Appl Chem

, 2003.⁷

To learn more about postreceptor signaling effects for each member of the VEGFR family of receptors, click on the links in the table below.

Receptor	Effects
VEGFR-1	Possible "decoy receptor" effect Induction of other factors
VEGFR-2	Proliferation Migration Survival Angiogenesis
VEGFR-3	Effects mainly in lymphatic cells

Signaling through VEGFR-1

Though this was the first vascular endothelial growth factor (VEGF) receptor (VEGFR) to be identified, its function is still somewhat controversial.^2,8

VEGFR-1 reveals a weak tyrosine autophosphorylation in response to VEGF. Some researchers have proposed that VEGFR-1 is a decoy receptor, and that it does not generally transmit mitogenic signals. Instead, these researchers propose that VEGFR-1 sequesters VEGF and prevents it from binding to VEGFR-2.^2,3

Multiple findings also suggest that VEGFR-1 induces urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), matrix metalloproteinase-9 (MMP9), and release of vascular bed—specific growth factors.² Recent work by Lesslie and colleagues in colorectal cancer cell lines also suggests that VEGFR-1 promotes cancer cell migration through a pathway dependent on Src family kinases.⁹

Signaling through VEGFR-2

VEGFR-2 signaling

Downstream effects of the binding, dimerization, and activation of the VEGF/VEGFR-2 complex include endothelial cell survival (through the PI3K/Akt pathway), migration (through the p38MAPK pathway), and proliferation (through the Raf/MEK/Erk pathway). All of these effects promote tumor angiogenesis.¹

Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043. Reprinted with permission from the American Society of Clinical Oncology.

The mitogenic, angiogenic, and permeability-enhancing effects of vascular endothelial growth factor (VEGF) are primarily mediated through VEGF receptor-2 (VEGFR-2), which undergoes dimerization and phosphorylation following ligand binding. This activity promotes the proliferation, migration, and survival of endothelial cells.²

Specifically, the downstream signaling effects of VEGFR-2 binding include integrin activation via the PI3K/Akt pathway, as well as activation of the Raf/MEK/Erk pathway to induce endothelial cell growth.²

Signaling through VEGFR-3

Vascular endothelial growth factor (VEGF) receptor-3 (VEGFR-3) is associated with lymphangiogenesis. When VEGF ligands bind with VEGFR-3, the complex triggers proliferation, migration, survival, and lymphangiogenesis in lymphatic endothelial cells.²

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References:

1.

Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043.

2.

Ferrara N. Endocr Rev. 2004;25:581-611.

3.

Park JE, Chen HH, Winer J, et al. J Biol Chem. 1994;269:25646-25654.

4.

Gille H, Kowalski J, Yu L, et al. EMBO J. 2000;19:4064-4073.

5.

Zeng H, Dvorak HF, Mukhopadhyay D. J Biol Chem. 2001;276:26969-26979.

6.

Autiero M, Waltenberger J, Communi D, et al. Nat Med. 2003;9:936-943.

7.

Picard D. Pure Appl Chem. 2003;75:1743-1756.

8.

de Vries C, Escobedo JA, Ueno H, et al. Science. 1992;255:989-991.

9.

Lesslie DP III, Summy JM, Parikh NU, et al. Br J Cancer. 2006;94:1710-1717.