Insulin and IGF-1 receptor trafficking and signalling.

Receptor-mediated endocytosis governs the entry of receptors inside the cells. In the case of signalling receptors, e.g. tyrosine kinase receptors, the process is ligand-dependent and includes a series of surface events which determines the specificity of the internalization process and the activation of distinct signal transduction pathways. Tyrosine kinase receptors, e.g. the insulin/IGF-1 receptors, are initially located outside the internalization gates (the clathrin-coated pits) and concentrated on thin digitations of the cell surface: the microvilli. In the case of the insulin receptor, specific motifs of the beta subunit are responsible for anchoring the receptor to microvilli. However, the molecular mechanisms by which this motif mediates this anchoring are poorly understood and necessitate further studies. In particular, the association of insulin receptors with cytoskeletal elements or specific lipidic domains concentrated on microvilli (e.g. lipid rafts) are under investigation as these interactions may provide the appropriate environment for the transduction of the insulin metabolic effects. Upon ligand binding, activated insulin receptors complexed to insulin are released from microvilli, segregate in clathrin-coated pits and enter the cells. In endosomes, insulin is uncoupled from its receptor and recycles back to the cell surface, whereas the hormone is degraded in lysosomes thus terminating the wave of signalling. These steps participate in the biological activity of the hormone via: (1) a regulation of cell sensitivity to the hormone through a fine tuning of the number of surface receptors; (2) termination of the signalling by intracellular degradation of the ligands; and (3) giving the receptors access to plasma membrane domains and intracellular compartments from which distinct signalling pathways originate. Current studies are designed to compare the behaviour of IGF-1 receptors to that of insulin receptors to establish whether different localization on the plasma membrane, trafficking pathways and/or kinetics of signalling might explain the different biological activities of these two receptors.