Intercellular adhesion molecule 1 (ICAM-1) a novel co-receptor for c-Met

Abstract

In several transformed and normal cells the transmembrane protein CD44v6 is required for activation and downstream signalling of the hepatocyte growth factor (HGF) receptor c-Met. However in situations where CD44 is not expressed i.e. in hepatocytes or in CD44 knockout mice does the c-Met receptor collaborate with other transmembrane partners for its activation and signal transduction? The idea that such molecules exist that can overtake CD44 functions came from CD44 knock out mice, which display an essentially normal phenotype. In order to find an alternative co-receptor for c-Met I analysed c-Met activation in cells devoid of CD44v6, the human hepatocellular carcinoma cell line HepG2. In these cells I checked for features of CD44v6 required for c-Met activity (i) modulation of c-Met signal transduction via the actin cytoskeleton linker, the ezrin/radixin/moesin (ERM) proteins (ii) repression of c-Met activation through the extracellular matrix component, hyaluronic acid (HA) and (iii) complex formation with c-Met. Since I confirmed in competition and siRNA experiments the requirement of ERM proteins in c-Met downstream signalling and furthermore that HA can indeed repress signalling from c-Met in the HepG2 cells, I looked for the expression of candidate molecules that could mediate these functions. Such a protein screen identified the intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is a cell adhesion molecule implicated in binding to ERM proteins and HA. Antibody blocking and siRNA experiments confirmed that ICAM-1 is required for the activation of c-Met and signal transduction upon ligand stimulation by HGF. These results demonstrate a novel co-receptor for c-Met and suggests that it might substitute for CD44 functions in CD44 knockout mice.