CD146: a new partner for VEGFR2.

Arbiser JL. Efficacy of topical application of eosin for ulcer-ated hemangiomas.macologic blockade of Angiopoietin-2 is efficacious against model hemangiomas in mice. In this issue of Blood, Jiang et al identify the cell adhesion molecule CD146 as novel co-receptor for vascular endothelial growth factor receptor 2 (VEGFR2). 1 T he cell adhesion molecule CD146 was first described in 1987 because of its expression on malignant melanocytes and was correlated with a negative prognosis of melanoma patients. Based on sequence homology analysis, CD146 could be identified as a member of the cell adhesion molecules (CAMs) of the immu-noglobulin superfamily. Therefore, it is also known as M-CAM or Mel-CAM (melanoma cell adhesion molecule). Not long afterward, CD146 was identified as a cell-surface antigen of endothelial cells. CD146 became popular as marker of circulating endothelial cells (CECs), which are increased in pathologic conditions such as cardiovascular diseases, inflammation, or cancer. Through the use of activating and inhibiting antibodies, involvement of several intracellular pathways in CD146 signaling including focal adhesion kinase or p38 kinase was identified. In this regard, CD146 mediates cell-cell interactions and migration of endo-thelial cells. 2 Jiang et al demonstrate the direct binding between CD146 and VEGFR2 in coimmuno-precipitation experiments. Furthermore, they found that the interaction takes place in the extracellular protein domain as the antibody AA98, which recognizes an extracellular CD146 epitope could block the interaction between VEGFR2 and CD146. Introduction of a mutation in this protein domain confirmed this observation. In addition, evidence was provided that the interplay of CD146 with VEGFR2 is mandatory for functional VEGFR2 signaling. Using an anti-CD146 antibody or CD146 siRNA, VEGF-induced phosphorylation of VEGFR2 was suppressed in human umbilical vein endothelial cells. Furthermore, inhibition of CD146 resulted in abrogation of the downstream cascade of p38 and Akt signaling, whereas ERK signaling was not affected by anti-CD146 antibody or CD146 siRNA. VEGFR2 mediates the full range of VEGF responses in endothelial cells including proliferation , regulation of survival, migration, and vascular tube formation. VEGFR2 has multiple tyrosine phosphorylation sites, which may explain its manifold biologic functions. 3 For instance, phosphorylation of Tyr 1175 results in activation of protein kinase C and downstream induction of the ERK pathway leading to cell proliferation. 4 On the other hand, upon phosphorylation of tyrosine residue Tyr 1214 , tyrosine kinase Fyn is activated, which results in subsequent activation of Cdc42 and MAP kinase p38 inducing reorganization of the actin cytoskeleton …