Insulin Receptor Isoforms and Insulin Growth Factor-like Receptors: Implications in Cell Signaling, Carcinogenesis, and Chemoresistance

Abstract

This comprehensive review thoroughly explores the intricate involvement of insulin receptor (IR) isoforms and insulin-like growth factor receptors (IGFRs) in the context of the insulin and insulin-like growth factor (IGF) signaling (IIS) pathway. This elaborate system encompasses ligands, receptors, and binding proteins, giving rise to a wide array of functions, including aspects such as carcinogenesis and chemoresistance. Detailed genetic analysis of IR and IGFR structures highlights their distinct isoforms, which arise from alternative splicing and exhibit diverse affinities for ligands. Notably, the overexpression of the IR-A isoform is linked to cancer stemness, tumor development, and resistance to targeted therapies. Similarly, elevated IGFR expression accelerates tumor progression and fosters chemoresistance. The review underscores the intricate interplay between IRs and IGFRs, contributing to resistance against anti-IGFR drugs. Consequently, the dual targeting of both receptors could present a more effective strategy for surmounting chemoresistance. To conclude, this review brings to light the pivotal roles played by IRs and IGFRs in cellular signaling, carcinogenesis, and therapy resistance. By precisely modulating these receptors and their complex signaling pathways, the potential emerges for developing enhanced anti-cancer interventions, ultimately leading to improved patient outcomes.

Keywords: IGF signal transduction; chemoresistance; insulin growth factor-like receptors; insulin receptor isoforms; insulin signal transduction.

Figure 1

The formation of IR isoforms: (1) Gene expression: INSR gene encoding IR is transcribed from DNA in the nucleus. (2) Pre-mRNA splicing involving introns’ removal and exclusion/inclusion of E11 to form mature mRNA molecules that encode either IR-A or IR-B isoforms; this process is regulated by specific splicing factors that bind to cis-acting elements in the pre-mRNA. (3) mRNA export from the nucleus to the cytoplasm through nuclear pores to serve as templates for protein synthesis. (4) mRNA Translation for IR synthesis. (5) Post-translational modifications (PTMs) in the endoplasmic reticulum and Golgi apparatus, including glycosylation, disulfide bond formation, and proteolytic cleavage. (6) Protein trafficking and secretion: mature IR isoforms are transported from the ER to the plasma membrane, where they are inserted and anchored by transmembrane domains. This process occurs through vesicular transport and fusion with the plasma membrane. Once inserted into the plasma membrane, IR isoforms are available for ligand binding and downstream signaling.

Figure 2

Structure of IR receptors. (A) Illustration showing different IR domains encoded by the 22 exons. IR has two main subunits: α and β. The α subunit contains 5 main domains, L1 (AA 28–174) CR (AA 182–339), and L2 (AA 340–497), and 2 Fibronectin subunits: FnIII-1 (residue 624–726) and FnIII-2 (757–842). The two α-subunits are linked by a disulfide bond between the two Cys 524 in the first FnIII domain. One to three of the triplet Cys at 682, 683, and 685 in the insert within the second FnIII domain are also involved in α-α disulfide bridges. There is a single disulfide bridge between α and β subunits between Cys 647 in the insert domain and Cys 872. The β subunit details are explained in the main text. Teal arrow shows 6 O-glycosylations, whereas the pink arrows imply the N-glycosylation. (B) IR-B amino acid sequence colored to identify each domain sequence presented in (A). (C) 3D structure of IR-B showing the Λ-shaped structure when no ligand is bound to it. (D) Structural differences between IR-A and IR-B. JM: Juxtamembrane, TK: Tyrosine Kinase. The 3D models were created using Swiss Model.

Figure 3

Hypothetical mechanisms of IR receptor activation upon ligand binding as proposed in the literature. (A) Ward et al. [40]; (B) Lee et al. [99]; (C) Kavran et al. [100]; (D) Maruyama et al. [97].

Figure 4

An illustration of the downstream pathways upon activation of IR and IGF-IR in physiological conditions. Specific differences between the receptors’ signaling pathways are explained in the text. Red circles are phosphorylation; green lines are excitatory signals; red lines are inhibitory signals.