How IGF-1 activates its receptor

Abstract

The type I insulin-like growth factor receptor (IGF1R) is involved in growth and survival of normal and neoplastic cells. A ligand-dependent conformational change is thought to regulate IGF1R activity, but the nature of this change is unclear. We point out an underappreciated dimer in the crystal structure of the related Insulin Receptor (IR) with Insulin bound that allows direct comparison with unliganded IR and suggests a mechanism by which ligand regulates IR/IGF1R activity. We test this mechanism in a series of biochemical and biophysical assays and find the IGF1R ectodomain maintains an autoinhibited state in which the TMs are held apart. Ligand binding releases this constraint, allowing TM association and unleashing an intrinsic propensity of the intracellular regions to autophosphorylate. Enzymatic studies of full-length and kinase-containing fragments show phosphorylated IGF1R is fully active independent of ligand and the extracellular-TM regions. The key step triggered by ligand binding is thus autophosphorylation.DOI: http://dx.doi.org/10.7554/eLife.03772.001

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

“…The very low sequence conservation for IFNAR1 is in line with the findings of this study that the TMD and its immediate surroundings serve merely as a bridge between the extracellular and cytoplasmic domain that does not convey a structural signal. This is fundamentally different from the suggested mechanism of EPOR, IL6R2, and VEGFR2 activation, where ligand-induced structural perturbations of the intracellular domains were suggested to play a key role in signaling (26,28,32).…”

Controlled dimerization of insulin-like growth factor-1 and insulin receptors reveals shared and distinct activities of holo and hybrid receptors

“…IGF1R and InsR are both tetrameric proteins composed of two extracellular α subunits covalently linked to two intracellular β subunits, which contain the tyrosine kinase domains (6,7). The binding of ligands to IGF1R and InsR leads to conformational changes in structure and transphosphorylation, which triggers the activation of two main cascades: the phosphatidylinositol 3-kinase/AKT kinase (PI3K/AKT) pathway and the RAF kinase/mitogen activated protein kinase (RAF/MAPK) pathway (4).…”

Participación del sistema IGF en la patogenia de la enfermedad quística bovina

“…Se une con alta afinidad a IGF1, en menor grado a IGF2 y con muy baja afinidad a la insulina (Giudice, 1992;Jones y Clemmons, 1995;Monget et al, 2002). Cuando el IGF1 se une a su receptor específico, IGFR1, se produce un cambio conformacional activándolo y provocando una cascada de fosforilación intracelular (Kavran et al, 2014). Si bien la insulina y el IGF1 poseen receptores diferentes, altas concentraciones de insulina pueden reconocer al IGFR1, y cuando ambos receptores están presentes en la misma célula son capaces de formar híbridos IGFR-IR (Figura 1), los cuales unen tanto IGF1 como insulina (Webb et al, 2004).…”

“…El ligando se une a su receptor específico, se produce un cambio conformacional y de esta manera se activa (Kavran et al, 2014). Una vez activado comienza una cascada de señalización que media el cre-IGF and COD pathogenesis cimiento folicular y la inhibición de la apoptosis (Kwiontkiewicz y Giudice, 2009;Sánchez et al, 2014), entre otras acciones.…”

“…Algunos estudios sugieren que el 17 β-estradiol estimularía la proliferación celular mediante la activación del IGFR1 independiente de los ligandos (Song et al, 2004, KamangaSollo et al, 2013. Sin embargo, otros autores postulan que la actividad de este receptor es dependiente del ligando, el IGF se une, produce un cambio conformacional provocando su activación (Kavran et al, 2014). Así, los altos niveles de IGFR1 en quistes podrían estar estimulados por los niveles de 17 β-estradiol tendientes a aumentar en estas estructuras (Amweg et al, 2013), cuando las concentraciones de IGF1 son bajas como ha sido demostrado previamente en quistes (Ortega et al, 2008).…”