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Isoform-and paralog-switching in IR-signaling: When diabetes opens the gates to cancer
Scalia, P Giordano, A Martini, C Williams, SJ
Scalia, P
Giordano, A
Martini, C
Williams, SJ
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Review
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2020-12-01
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HIF: hypoxia-inducible factor
IGF: insulin-like growth factor
IR: insulin receptor
Isoform: for the scope of this review, the term isoform is restricted to products of alternatively spliced coding genes
MAPK-ERK: Mitogen-activated protein Kinase-Extracellular-signal-regulated Kinase
Paralog: the product of gene variants with high sequence similarity encoded by duplicated genes in the genome
IGF: insulin-like growth factor
IR: insulin receptor
Isoform: for the scope of this review, the term isoform is restricted to products of alternatively spliced coding genes
MAPK-ERK: Mitogen-activated protein Kinase-Extracellular-signal-regulated Kinase
Paralog: the product of gene variants with high sequence similarity encoded by duplicated genes in the genome
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10.3390/biom10121617
Abstract
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Insulin receptor (IR) and IR-related signaling defects have been shown to trigger insulin-resistance in insulin-dependent cells and ultimately to give rise to type 2 diabetes in mammalian organisms. IR expression is ubiquitous in mammalian tissues, and its over-expression is also a common finding in cancerous cells. This latter finding has been shown to associate with both a relative and absolute increase in IR isoform-A (IR-A) expression, missing 12 aa in its EC subunit corresponding to exon 11. Since IR-A is a high-affinity transducer of Insulin-like Growth Factor-II (IGF-II) signals, a growth factor is often secreted by cancer cells; such event offers a direct molecular link between IR-A/IR-B increased ratio in insulin resistance states (obesity and type 2 diabetes) and the malignant advantage provided by IGF-II to solid tumors. Nonetheless, recent findings on the biological role of isoforms for cellular signaling components suggest that the preferential expression of IR isoform-A may be part of a wider contextual isoform-expression switch in downstream regulatory factors, potentially enhancing IR-dependent oncogenic effects. The present review focuses on the role of isoform-and paralog-dependent variability in the IR and downstream cellular components playing a potential role in the modulation of the IR-A signaling related to the changes induced by insulin-resistance-linked conditions as well as to their relationship with the benign versus malignant transition in underlying solid tumors.
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