Insulin and insulin like growth factor II endocytosis and signaling via insulin receptor B
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RESEARCH
Open Access
Insulin and insulin like growth factor II endocytosis and signaling via insulin receptor B Jimena Giudice1,2,6, Lucia Soledad Barcos1, Francisco F Guaimas1, Alberto Penas-Steinhardt3, Luciana Giordano4, Elizabeth A Jares-Erijman2ˆ and Federico Coluccio Leskow1,5*
Abstract Background: Insulin and insulin-like growth factors (IGFs) act on tetrameric tyrosine kinase receptors controlling essential functions including growth, metabolism, reproduction and longevity. The insulin receptor (IR) binds insulin and IGFs with different affinities triggering different cell responses. Results: We showed that IGF-II induces cell proliferation and gene transcription when IR-B is over-expressed. We combined biotinylated ligands with streptavidin conjugated quantum dots and visible fluorescent proteins to visualize the binding of IGF-II and insulin to IR-B and their ensuing internalization. By confocal microscopy and flow cytometry in living cells, we studied the internalization kinetic through the IR-B of both IGF-II, known to elicit proliferative responses, and insulin, a regulator of metabolism. Conclusions: IGF-II promotes a faster internalization of IR-B than insulin. We propose that IGF-II differentially activates mitogenic responses through endosomes, while insulin-activated IR-B remains at the plasma membrane. This fact could facilitate the interaction with key effector molecules involved in metabolism regulation. Keywords: Insulin / IGF-II, Insulin receptor, Microscopy, Quantum dots, Endocytosis, Signaling
Lay abstract Background: The insulin receptor (IR) responds to insulin and IGF-II regulating glucose metabolism, cellular growth and differentiation. Results: Using quantum dotconjugated IGF-II and insulin we analyzed IR-B endocytosis in correlation with mitogenicity of each ligand. Conclusions: IGF-II promotes a fast IR internalization favoring mitogenic signaling whereas insulin-activated IR would endures signaling from the membrane. Significance: Ligand-specific redistribution of activated IR ensures signal specificity. Background Insulin and insulin-like growth factors (IGFs) are polypeptide hormones common to all metazoans [1]. They control essential functions including growth, metabolism, * Correspondence: [email protected] ˆDeceased 1 Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), IQUIBICEN, CONICET, Buenos Aires, Argentina 5 Departamento de Ciencias Básicas, Universidad Nacional de Luján, Argentina Full list of author information is available at the end of the article
reproduction and longevity which are triggered by activation of tetrameric tyrosine kinase receptors [2-9]. During vertebrate and invertebrate embryonic development, insulin and IGFs act as mitogenic growth factors. In postnatal vertebrates, insulin acts as a specialized metabolic hormone regulating glucose homeostasis, whereas IGFs retain their mitogenic functions. Invertebrates possess several insulin-like growth factors genes but only one rece
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