| Literature References | 1. CONNOLLY, D.T., HEUVELMAN, D.M., NELSON, R., OLANDER, J.V., EPPLEY, B.L.,
DELFINO, J.J., SIEGEL, N.R., LEIMGRUBER, R.M. AND FEDER, J.
Tumor vascular permeability factor stimulates endothelial cell growth and
angiogenesis.
J.CLIN.INVEST. 84 1470-1478 (1989).
2. AIELLO, L.P., AVERY, R.L., ARRIGG, P.G., KEYT, B.A., JAMPEL, H.D.,
SHAH, S.T., PASQUALE, L.R.,THIEME, H., IWAMOTO, M.A. AND PARK, J.E.
Vascular endothelial growth factor in ocular fluid of patients with diabetic
retinopathy and other retinal disorders.
N.ENGL.J.MED. 331 1480-1487 (1994).
3. MUSTONEN, T. AND ALITALO, K.
Endothelial receptor tyrosine kinases involved in angiogenesis.
J.CELL.BIOL. 129 895-898 (1995).
4. IRRTHUM, A., KARKKAINEN, M.J., DEVRIENDT, K., ALITALO, K. AND VIKKULA, M.
Congenital hereditary lymphedema caused by a mutation that inactivates
VEGFR3 tyrosine kinase.
AM.J.HUM.GENET. 67 295-301 (2000).
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| Documentation | Vascular endothelial growth factor (VEGF) is a potent and specific
endothelial cell mitogen [1]. Through binding with its receptor, VEGFR, VEGF
has critical roles in the growth and maintenance of vascular endothelial
cells and in the development of new blood- and lymphatic-vessels in
physiological and pathological states [2]. The vessel systems are important
for the supply of oxygen and nutrients to all tissues of the body, as well
as for the drainage of excess fluids with waste metabolites from peripheral
tissues. VEGF receptors have a characteristic structure, with 7 Ig-like
domains in the extracellular domain and a cytoplasmic tyrosine kinase domain
with a long kinase insert region.
The VEGF receptor family consists of three members, VEGFR-1 (Flt-1), VEGFR-2
(KDR/Flk-1) and VEGFR-3 (Flt-4), all of which belong to the receptor type
tyrosine kinase superfamily [3]. Among these receptors, VEGFR-1 binds
strongest to VEGF, VEGF-2 binds more weakly, and VEGFR-3 shows essentially
no binding, although it does bind to other members of the VEGF family.
In humans, an A to G transition corresponding to a histidine to arginine
substitution in the catalytic loop of VEGFR3 has been linked to congenital
hereditary lymphedema. In vitro expression studies show that this amino acid
substitution causes loss of VEGFR3 tyrosine kinase acivity. Thus, defective
VEGFR3 signalling is responsible for 5q34-q35-linked congenital hereditary
lymphedema [4].
VEGFRECEPTR3 is a 7-element fingerprint that provides a signature for the
type 3 vascular endothelial growth factor receptors. The fingerprint was
derived from an initial alignment of 3 sequences: the motifs were drawn from
conserved regions spanning the N-terminal half of the extracellular domain,
focusing on those sections that characterise the VEGFR3 subtypes, but
distinguish them from the rest of the VEGFR family - motif 1 lies in the
N-terminal signalling region; and motifs 4, 6 and 7 reside within Ig domains
2, 3 and 5 respectively. Two iterations on SPTR40_20f were required to reach
convergence, at which point a true set comprising 5 sequences was identified.
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