Abstract
Insulin (InsR) and insulin-like growth factor-1 (IGF1R) receptors mediate the metabolic and growth-promoting actions of insulin and IGF1/IGF2, respectively. Evidence accumulated in recent years indicates that, in addition to their typical cell-surface localization pattern and ligand-activated mechanism of action, InsR and IGF1R are present in the cell nucleus of both normal and transformed cells. Nuclear translocation seems to involve interaction with a small, ubiquitin-like modifier protein (SUMO-1), although this modification is not always a prerequisite. Nuclear InsR and IGF1R exhibit a number of biological activities that classically fit within the definition of transcription factors. These nuclear activities include, among others, sequence-specific DNA binding and transcriptional control. Of particular interest, nuclear IGF1R was capable of binding and stimulating its cognate gene promoter. The physiological relevance of this autoregulatory mechanism needs to be further investigated. In addition to its nuclear localization, studies have identified IGF1R in the Golgi apparatus, and this particular distribution correlated with a migratory phenotype. In summary, the newly described roles of InsR and IGF1R as gene regulators, in concert with their atypical pattern of subcellular distribution, add a further layer of complexity to traditional models of cell signaling. Furthermore, and in view of the emerging role of IGF1R as a potential therapeutic target, a better understanding of the mechanisms responsible for nuclear IGF1R transport and identification of IGF1R interactors might help optimize target directed therapies in oncology.
Highlights
The ability of insulin receptor (InsR) and IGF1 receptor (IGF1R) to function as sical models of cell signaling by: (1) identifying tyrosine kinase cell-surface receptors in transcriptional activators has been confirmed in recent years by a number of laboratories
The identification of InsR and IGF1R in the nucleus of normal and cancer cells has generated a significant level of interest in recent years [73,74]
While nuclear insulin binding was first described more than 45 years ago, the recognition that classical cell-surface tyrosine kinase receptors can migrate to the cell nucleus and function as bona fide transcription factors stood against firmly established dogmas in signal transduction
Summary
The insulin-like growth factors (IGFs) are a family of mitogenic growth factors, cellsurface receptors and binding proteins that are involved in normal growth, development and differentiation of most organs and tissues as well as in a number of pathological conditions [1,2]. Postnatal stages are characterized by a drastic reduction in circulating and tissue IGF2 levels These early observations led to an erroneous generalization of the roles of IGF2 and IGF1 as fetal and pubertal growth factors, respectively. In humans, both ligands are produced from prenatal to postnatal stages and, endocrine. The vast majority of circulating IGF1 and IGF2 is found in a ternary complex with IGFBP3 and an acid labile subunit [16] This complex modulates IGF action by protecting the growth factors from proteolysis and prolonging their half lives in body fluids [17]. Some IGFBPs exert a number of biological effects in an IGF-independent manner [18]
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