血管内皮細胞増殖因子受容体Flt-1のエンドサイトーシス

抄録

Vascular endothelial growth factor (VEGF) has two receptors with catalytic activity: Flt-1 and KDR. The uniqueness of Flt-1 is that it is also expressed in macrophages and plays an essential role in atherosclerosis. Given that oxidized LDL and proteasome inhibitors appeared to down-regulate the Flt-1 expression, regulation of Flt-1 on the cell surface as for example a VEGF-trapping molecule for KDR may have a close linkage with initiation of atherosclerotic plaque formation. We have shown that Flt-1 is endocytosed upon binding to VEGF as in the case of other tyrosine kinase growth factor receptors. The minor autophosphorylation site Y 1333 seems to be utilized for recruiting the c-Cbl/CD2AP complex to Flt-1. c-Cbl is an E3 ligase that ubiquitinates Flt-1 with subsequent degradation in proteasomes. Although CD2AP overexression changes endosomal morphology and therefore it appears to be involved in vesicle formation, the precise mechanisms and biological roles of endocytosis still remain to be elucidated. Inhibitors for heat shock protein (Hsp) 90, which is assumed to stabilize the degrading molecule, induced a seemingly VEGF-independent degradation of Flt-1. In this paper, we hopefully discuss possible biological significance and molecular mechanisms of Flt-1 disappearance from the cell surface from the standpoint of atherosclerosis. [J Physiol Sci. 2006;56 Suppl:S8]