THE DIFFERENTIAL ENDOCYTOSIS DYNAMICS OF THE INSULIN RECEPTOR (IR) SPLICE VARIANTS REGULATES MITOGENIC AND METABOLIC SIGNALING

JIMENA GIUDICE; THOMAS M. JOVIN; FEDERICO COLUCCIO LESKOW; ELIZABETH JARES-ERIJMAN

Buenos Aires

Congreso; XII Jornadas Multidisciplinarias de la Sociedad Argentina de Biología; 2010

Sociedad Argentina de Biología

Insulin signalling comprises a complex cascade of events playing a key role in the regulation of glucose metabolism and cellular growth. Failures in its function lead to diabetes and disregulations of these pathways were described in many cancer types. The IR is a tetrameric receptor tyrosine kinase. Two splice variants exist in mammalian cells: IR-A lacking exon 11, and the full length IR-B. The main goal of this work is the study of the dynamics of the activation and internalization of the IR. We generated recombinant IR fused to different visible fluorescent proteins without affecting functionality. Biotinylated insulin in combination with fluorescent nanoparticles (streptavidin-quantum dots) allowed us to study IR dynamics after insulin binding by microscopy and flow citometry.  These showed that IR-A is internalized more rapidly than IR-B. These differences correlated with higher and sustained activation of IR-A in response to insulin and distinctive ERK 1/2 activation profiles and gene transcription regulation. On the other hand IR-B triggered a higher AKT signaling which is involved in metabolism regulation. These results support a model of diferential localization of the IR signaling: while internalized receptors regulate mitogenic activity, surface receptors are responsible of the metabolic balance regulation.receptors are responsible of the metabolic balance regulation.