Insulin receptor membrane retention by a traceable chimeric mutant
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RESEARCH
Open Access
Insulin receptor membrane retention by a traceable chimeric mutant Jimena Giudice1,2,4, Elizabeth A Jares-Erijman2ˆ and Federico Coluccio Leskow1,3*
Abstract Background: The insulin receptor (IR) regulates glucose homeostasis, cell growth and differentiation. It has been hypothesized that the specific signaling characteristics of IR are in part determined by ligand-receptor complexes localization. Downstream signaling could be triggered from the plasma membrane or from endosomes. Regulation of activated receptor's internalization has been proposed as the mechanism responsible for the differential isoform and ligand-specific signaling. Results: We generated a traceable IR chimera that allows the labeling of the receptor at the cell surface. This mutant binds insulin but fails to get activated and internalized. However, the mutant heterodimerizes with wild type IR inhibiting its auto-phosphorylation and blocking its internalization. IR membrane retention attenuates AP-1 transcriptional activation favoring Akt activation. Conclusions: These results suggest that the mutant acts as a selective dominant negative blocking IR internalization-mediated signaling. Keywords: Insulin receptor, Membrane retention, Dominant negative, Endocytosis
Background Insulin receptor (IR) is a tetrameric tyrosine kinase receptor involved on glucose homeostasis, cell growth and differentiation. Two IR variants are produced in mammals by alternative splicing: IR-A lacking exon 11 and the full length IR-B [1,2]. While IR-B is widely expressed in adult tissues, embryos predominantly express IR-A where it functions as a regulator of cellular proliferation and differentiation [3]. Alterations in the ratio of IR isoform expression have been associated with cellular dysregulation and disease. Some reports showed that in diabetic patients there are differences at the mRNA level in the IR-A/IR-B ratio in skeletal muscle [4,5], however this was not observed by others [6-8]. Cancer cells commonly express the IR-A subtype [9-12]. In addition, there are differences in the activation and signaling * Correspondence: [email protected] ˆDeceased 1 Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA) IQUIBICEN, CONICET, Intendente Güiraldes 2160, Ciudad Universitaria, C1428EGA Buenos Aires, Argentina 3 Departamento de Ciencias Básicas, Universidad Nacional de Luján, Buenos Aires, Argentina Full list of author information is available at the end of the article
events between the two isoforms, indicating specific functions [13-15]. Using an elegant harmonic oscillator mathematical model, Knudson et al. reported that insulin has 1.5-fold higher affinity and a 2-fold higher dissociation rate for IR-A, than for IR-B [16]. On the other hand, IR-B binds insulin with higher affinity than for insulin like growth factor II (IGF-II) [3]. Additionally, it has been recently shown that IR-A binds IGF-II with a lower affinity than insulin [17], in contrast with a previous repo
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