Insulin and insulin like growth factor II endocytosis and signaling via insulin receptor B

Jimena Giudice,Federico Coluccio Leskow,Alberto Penas-Steinhardt,Francisco F Guaimas,Luciana Giordano,Lucia Soledad Barcos,Elizabeth A Jares-Erijman

doi:10.1186/1478-811x-11-18

Abstract

BackgroundInsulin 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.ResultsWe 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.ConclusionsIGF-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.

Highlights

Insulin and insulin-like growth factors (IGFs) act on tetrameric tyrosine kinase receptors controlling essential functions including growth, metabolism, reproduction and longevity
IGF-II promotes a fast insulin receptor (IR) internalization favoring mitogenic signaling whereas insulin-activated IR would endures signaling from the membrane
IGF-II induces Insulin receptor isoform B (IR-B) phosphorylation We evaluated the effect of IGF-II on IR-B activation by confocal microscopy and Western blot

Summary

Introduction

Insulin and insulin-like growth factors (IGFs) act on tetrameric tyrosine kinase receptors controlling essential functions including growth, metabolism, reproduction and longevity. Insulin and insulin-like growth factors (IGFs) are polypeptide hormones common to all metazoans [1]. They control essential functions including growth, metabolism, IGF-I and IGF-II are produced primarily by the liver. IGFs bind to the IGF-IR, expressed in almost all cell types, promoting cellular growth and proliferation and inhibiting apoptosis. These growth factors stimulate DNA synthesis and regulate development and differentiation in a large variety of cell types, playing a key role in the maximum size acquired by an organism. It was shown that a population carrying mutations in the growth hormone receptor gene has lower expression levels of the growth hormone receptor and IGF-I, while exhibiting a very low incidence of cancer and absence of diabetes [23]

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