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Molecular Mechanisms of Brain Insulin Signaling 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Simran Chopra, Robert Hauffe, André Kleinridders
The main negative modulator responsible for fine-tuning insulin signaling is the tyrosine-protein phosphotase non-receptor type 1 (PTP1B). PTP1B directly dephosphorylates tyrosine residues of the insulin receptor, thereby stopping the downstream activation of IRS proteins. IRS itself can be dephosphorylated by PTPN11 (also known as SHP-2) (Figure 1.3). Furthermore, the metabolite PIP3 is subject to dephosphorylation by Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase (PTEN), and Phosphatidylinositol 3,4,5- trisphosphate 5-phosphatase 1 (SHIP), that subsequently stops the signaling cascade (Figure 1.3). Downstream of the insulin signaling cascade, AKT can be deactivated by serine/threonine-protein phosphatase 2A catalytic subunit alpha (PP2a). Furthermore, AKT can be dephosphorylated by PH domain and Leucine-rich repeat Protein Phosphatase (PHLPP), which dephosphorylate AKT on Ser473, which is a phosphorylation site needed for the full activation of AKT (Figure 1.3). However, it needs to be stated that these feedback systems, that act on all levels of the signaling cascade, serve a vital role in limiting the cellular response to insulin (64). It is readily imaginable that unchecked activation of insulin signaling and the subsequently engaged energy-consuming processes, such as protein synthesis, growth, and proliferation could quickly lead to detrimental outcomes for the cells. Indeed, loss of function mutations in PTEN for example lead to a loss of feedback inhibition, which is the underlying cause of a variety of diseases collectively called PTEN hamartoma tumor syndromes (PHTS). These syndromes are characterized by the inability of cells to stop cell division, which leads to the growth of non-cancerous tumors (hamartoma) and a substantial life-long risk of cancer, particularly in the breast, thyroid, or uterus (65). Moreover, in the Cowden syndrome, which is part of the PHT syndrome, over 80% of patients show neurodevelopmental disorders, such as macrocephaly or hemimegalencephaly (66). Furthermore, an estimated 70% of prostate cancer patients have lost at least one gene copy of PTEN at the time of diagnosis (67). Similarly, hyperactivation of AKT, or gene amplification leading to higher total AKT functionality, has been described in a variety of cancers, such as gastric, breast, ovarian, pancreatic, colon, esophageal, and thyroid cancers (comprehensively reviewed by Mundi et al. (68)). Additionally, it has been found that gain of function mutations of AKT that result in its hyperactivation lead to forms of Juvenile Granulosa Cell tumors (JGCT). Mechanistically, in-frame duplications within the PH domain of AKT lead to higher-than-normal distribution at the cell membrane and an increased degree of activating phosphorylation (69, 70).
Chaperone-mediated autophagy as a therapeutic target for Parkinson disease
Published in Expert Opinion on Therapeutic Targets, 2018
Philip Campbell, Huw Morris, Anthony Schapira
It has been shown that a pair of proteins, GFAP and EF1ɑ, acting in a GTP dependent manner can modulate the assembly/disassembly rate of the LAMP2A translocation complex [73]. Association of GFAP to the translocation complex contributes to its stabilization. Once the substrate has passed through the complex GFAP dissociates and binds to phosphorylated forms of GFAP which are found bound to EF1ɑ, this promotes disassembly of the translocation complex and so a reduction in CMA flux [73]. A further layer of complexity has been added recently with the finding that CMA activity is regulated by the lysosomal mTORC2/PHLPP1/Akt axis [74]. Here mTORC2 acts as an inhibitor with PHLPP1 acting as a stimulator of CMA under stress conditions, likely mediated through the phosphorylation of GFAP [74]. The number of cellular processes involving PHLPP1 is enlarging [75] which may well limit it as a target for therapeutic intervention due to off target effects. Similarly, unlike the closely related mTORC1 (which interestingly is involved in the regulation of macroautophagy), mTORC2 signaling is less well understood but appears to be involved in a diverse range of processes that suggest inhibition may have detrimental consequences [76,77]. Currently there are no small molecules that specifically target mTORC2, but encouragingly competitive inhibitors of mTOR that inhibit both mTORC1 and mTORC2 are being investigated in oncology clinical trials and so appear to be tolerated by human subjects [78].