Table 1 PTKs and their role in lymphatic biology

VEGFR-2

Receptor for the VEGF family of ligands. Can also heterodimerize with VEGFR-3.

Yes

Secreted VEGFR-2 is a naturally occurring inhibitor of lymphatic vessel growth.

However, Sorafenib^† did not block VEGF-C/D induced tumor lymphangiogenesis.

[132, 133]

VEGFR-3

Predominant receptor for the lymphangiogenic growth factors VEGF-C and VEGF-D, transduces survival, proliferation and migration signals.

Yes

Cediranib^‡ blocks VEGFR-3 activity and inhibits lymphangiogenesis.

Anti-VEGFR-3 antibody prevented tumor lymphangiogenesis with no effect on preexisting vessels.

[32, 33, 88, 134–136]

Tie1

Not critical for lymphatic cell commitment during development, and no ligand has been shown.

None reported

Tie1 knockout mouse has lymphatic vascular abnormalities that precede the blood vessel phenotype.

[55]

Tie2

Receptor for Ang-1 and Ang-2, appears to control vessel maturation.

Yes

Tie2^-/- mice are embryonic lethal due to vascular defects.

Inhibition of Ang-2 leads to tumor blood vessel normalization.

[49, 50, 137]

EphB4

Expressed on lymphatic capillary vessels, involved in vascular patterning, binds to the ephrinB2 ligand.

Yes

Mice expressing a mutant form of ephrinB2 lacking the PDZ binding domain show major lymphatic defects in capillary vessels and collecting vessel valve formation.

[60]

SRC

Signal transduction downstream from receptors.

Yes

Src inhibitor AZM475271 was effective at blocking VEGF-C driven lymphangiogenesis in vivo.

[103]

FGFR3

The ligands FGF-1 and FGF-2 promote proliferation, migration, and survival of cultured LECs. FGFR3 is direct transcriptional target of Prox1.

Yes

Knockdown of FGFR3 reduced LEC proliferation.

[47]

IGF1R

Both of the IGF1R ligands, IGF-1 and IGF-2, significantly stimulated proliferation and migration of primary lymphatic endothelial cells.

Yes

None reported.

[48]

PDGFRβ

The ligand PDGF-BB stimulated MAP kinase activity and cell motility of isolated lymphatic endothelial cells.

Yes

None reported.

[138]

MET

The ligand for c-Met, hepatocyte growth factor has lymphangiogenic effect, but it is unclear if c-Met is expressed on LECs.

Yes

May be indirect effect.

[45, 46]