Ubiquitylation Pathways In Insulin Signaling and Organismal Homeostasis

Abstract

The insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) pathway is a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms. IIS integrates a fine-tuned cascade of signaling events induced by insulin/IGF-1, which is precisely controlled by post-translational modifications. The ubiquitin/proteasome-system (UPS) influences the functionality of IIS through inducible ubiquitylation pathways that regulate internalization of the insulin/IGF-1 receptor, the stability of downstream insulin/IGF-1 signaling targets, and activity of nuclear receptors for control of gene expression. An age-related decline in UPS activity is often associated with an impairment of IIS, contributing to pathologies such as cancer, diabetes, cardiovascular, and neurodegenerative disorders. Recent findings identified a key role of diverse ubiquitin modifications in insulin signaling decisions, which governs dynamic adaption upon environmental and physiological changes. In this review, we discuss the mutual crosstalk between ubiquitin and insulin signaling pathways in the context of cellular and organismal homeostasis.

Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

“…FoxO1, β-arrestin, IRS and IGF1R are all crucial to maintaining an efficient insulin signal (Usui et al, 2004;Girnita et al, 2007). Interestingly, these proteins might compete for binding to MDM2 (Balaji et al, 2018). Yet, the role of cardiac MDM2 in diabetic cardiomyopathy remains unclear.…”

Carbidopa suppresses prostate cancer via aryl hydrocarbon receptor-mediated ubiquitination and degradation of androgen receptor

“…The ubiquitin-proteasome system, which regulates cellular protein degradation, plays a pivotal role in cellular homeostasis 30 . Previous studies have shown that AHR acts as an E3 ubiquitin ligase to modulate steroid receptor functions 31 .…”

Growth Hormone Receptor Regulation in Cancer and Chronic Diseases

“…CHIP is an E3 ubiquitin ligase that plays a pivotal role in the protein quality control system by shifting the balance of the folding-refolding machinery toward the degradative pathway in order to maintain balanced proteostasis networks (33,(210)(211)(212). CHIP is highly expressed in tissues with high metabolic activity and protein turnover.…”

“…Remarkably, transcription of CHIP is also modulated in response to changes in AKT levels (215). Similar to AKT regulation, CHIP indirectly impacts the FOXO function on various levels through modulation of upstream substrates of the insulin/IGF-1 signaling pathway, a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms (210). Thus, CHIP integrates proteostasis and aging by regulation the turnover of the INSR (211).…”

“…Accordingly, Ames dwarf mice produce less metabolic oxidants, and have increased levels of anti-oxidants (284,285). On the other hand, in GH-deficient humans, insulin resistance increases the oxidative damage (282), induces accumulation of visceral fat mass (286), and increases the risk of several agerelated diseases (12,210,287). Thus, differences in the aging process between mice and humans suffering from GH-deficiency may be explained by their difference in insulin sensitivity.…”