Abstract
A number of studies performed on rodents suggest that insulin-like growth factor 2 (IGF-2) or its analogs may possibly be used for treating some conditions like Alzheimer’s disease, Huntington’s disease, autistic spectrum disorders or aging-related cognitive impairment. Still, for translational research a comparative knowledge about the function of IGF-2 and related molecules in model organisms (rats and mice) and humans is necessary. There is a number of important differences in IGF-2 signaling between species. In the present review we emphasize species-specific patterns of IGF-2 expression in rodents, humans and some other mammals, using, among other sources, publicly available transcriptomic data. We provide a detailed description of Igf2 mRNA expression regulation and pre-pro-IGF-2 protein processing in different species. We also summarize the function of IGF-binding proteins. We describe three different receptors able to bind IGF-2 and discuss the role of IGF-2 signaling in learning and memory, as well as in neuroprotection. We hope that comprehensive understanding of similarities and differences in IGF-2 signaling between model organisms and humans will be useful for development of more effective medicines targeting IGF-2 receptors.
Highlights
Received: 7 January 2021Insulin, insulin-like growth factors 1 and 2 (IGF-1, insulin-like growth factor 2 (IGF-2)), their receptors and IGFbinding proteins (IGFBPs) comprise an integrated system of signal molecules working on auto, para- and endocrine levels and participating in multiple metabolic, trophic and protective functions, from embryonic development to homeostasis maintenance in adult organism [1,2,3,4]
Which proteases are responsible for cleaving pro-IGF-2 to produce “big IGF-2” forms and mature IGF-2? Supposedly, these proteases belong to the proprotein convertase subtilisin/kexin type (PCSK) family
The studies demonstrating the role of IGF-2/IGF2R interaction in learning and memory are described in more detail in the section “IGF-2 as a memory enhancer” but here we provide a short summary
Summary
Insulin-like growth factors 1 and 2 (IGF-1, IGF-2), their receptors and IGFbinding proteins (IGFBPs) comprise an integrated system of signal molecules working on auto-, para- and endocrine levels and participating in multiple metabolic, trophic and protective functions, from embryonic development to homeostasis maintenance in adult organism [1,2,3,4]. Insulin is best known for its key role in glucose uptake in tissues [4] Both insulin-like growth factors were previously considered to mediate growth hormone effects [5,6] but currently only IGF-1 is believed to perform this function [7]. It was shown that cognitive and neuroprotective effects of IGF-2 are mediated by IGF2R [2,11,40,41,42] This receptor was for a long time considered to function as a scavenger mediating IGF-2 degradation and its signaling activity was not recognized [6,43,44] but a growing body of evidence suggests that IGF2R is able to trigger signaling pathways [15,45,46,47]. The present work provides the information which may be important for research and development of IGF2- or IGF2R-targeting strategies for treating various neuropathologies, including aging-related dysfunctions and neurodegenerative disorders
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