Adaptor molecules are non-catalytic polypeptides that contain one or more domains able to bind to other protein or non-protein ligands. These molecules selectively control the spatial and temporal assembly of multiprotein complexes that transmit intracellular signals involved in regulation of cell growth, differentiation, migration and survival. Cbl-interacting protein of 85 kDa (CIN85) is such a protein. It is known to be involved in receptor trafficking and cytoskeletal dynamics. The multitude of verified interaction partners has placed CIN85 as a central adaptor molecule involved in the recruitment of the endocytic machinery required for the internalization of a variety of cell surface receptors, including growth factor receptors (such as EGFR, Met and VEGFR), immunoglobulin IgE receptors in mast cells, as well as during the infectious internalization of the bacterial pathogen Listeria monocytogenes.
A mouse line deficient of the two CIN85 isoforms (CIN85Δex2) expressed in the central nervous system was analysed in the German Mouse Clinic. Mice deficient of brain-specific CIN85 expression show hyperactive phenotypes, which in many ways resemble the behavioural aberrations displayed in human beings affected by attention deficit hyperactivity disorder (ADHD), a disorder strongly associated with abnormal dopamine signalling. These behavioural changes became obvious on the modified holeboard where CIN85 Δex2 animals exhibited enhanced forward locomotor activity, manifested by an increase in total distance travelled, number of line crossings, mean and maximum velocity, as well as turning frequency. In addition, CIN85 Δex2 knockout mice showed enhanced exploratory behaviour — entering the board more frequently and exploring a larger number of holes on the board, than wild-type animals. Interestingly, CIN85 Δex2 animals display abnormally high levels of dopamine and D2 dopamine receptors in the striatum, an important centre for the coordination of animal behaviour.
Further comparisons of CIN85 Δex2 knockout and wild-type animals revealed deviations in several metabolic parameters, including increased energy uptake, higher lean mass and lower fat content. This might be expected since hyperactive animals need more energy to compensate.
These findings indicate an important function of CIN85 in the regulation of dopamine receptor functions and provide a molecular explanation for the hyperactive behaviour of CIN85 Δex2 mice.
CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice“, Shimokawa et al, Embo Journal, 2010 (29), 2421-2432