Abstract
The ligand-induced dimerization of cell surface single-transmembrane receptors is essential for their activation. However, physiological molecules that inhibit their dimerization and activation have not been identified. ErbB3 dimerizes with ErbB2 upon binding of heregulin (HRG) to ErbB3, causing the ErbB2-catalyzed tyrosine phosphorylation of ErbB3, which leads to the activation of the signalling pathways for cell movement and survival. Genetic disorders of this receptor cause tumorigenesis and metastasis of cancers. We show here that nectin-like molecule-4/cell adhesion molecule 4, known to serve as a tumour suppressor, interacts with ErbB3 in the absence of HRG and inhibits the HRG-induced dimerization of ErbB3 with ErbB2 and its activation. The third immunoglobulin-like domain of nectin-like molecule-4 cis-interacts with the extracellular domain 3 of ErbB3. We describe here a novel regulatory mechanism for the activation and signalling of cell surface single-transmembrane receptors.