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Insulin receptor membrane retention by a traceable chimeric mutant.

Jimena Giudice¹, Elizabeth A Jares-Erijman, Federico Coluccio Leskow

¹Departamento 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. federico@fbmc.fcen.uba.ar.

Cell Communication and Signaling : CCS

|June 29, 2013

Summary

A novel insulin receptor (IR) chimera blocks receptor internalization, revealing its critical role in signaling pathways. This discovery impacts understanding of glucose homeostasis and cell growth regulation.

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Published on: July 15, 2025

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Area of Science:

Cell biology
Molecular endocrinology
Signal transduction

Background:

The insulin receptor (IR) is crucial for regulating glucose homeostasis, cell growth, and differentiation.
IR signaling is influenced by ligand-receptor complex localization, with signaling originating from the plasma membrane or endosomes.
Receptor internalization is a proposed mechanism for differential, isoform, and ligand-specific signaling.

Purpose of the Study:

To investigate the role of insulin receptor internalization in regulating downstream signaling pathways.
To develop a tool for tracking insulin receptor localization and function.

Main Methods:

Generation of a traceable insulin receptor (IR) chimera for cell surface labeling.
Characterization of the chimera's binding, activation, and internalization properties.
Assessment of the chimera's effect on wild-type IR auto-phosphorylation and internalization.
Analysis of downstream signaling pathways, including AP-1 transcriptional activation and Akt activation.

Main Results:

The generated IR chimera binds insulin but is not activated or internalized.
The mutant IR chimera heterodimerizes with wild-type IR, inhibiting its auto-phosphorylation and internalization.
Retention of the IR at the cell membrane by the chimera attenuates AP-1 transcriptional activation while favoring Akt activation.

Conclusions:

The engineered IR chimera functions as a selective dominant-negative inhibitor.
This inhibition specifically blocks insulin receptor internalization-mediated signaling.
Findings highlight the importance of receptor internalization in directing specific signaling outcomes.