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Role and Molecular Mechanism of C1-Ten in Insulin Signaling

Role and Molecular Mechanism of C1-Ten in Insulin Signaling
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Insulin signaling has got the center of attention because of its implication with metabolic diseases like diabetes mellitus. It is estimated that about 300 million people worldwide will suffer from diabetes and this number will be doubled by 2030. There have been many efforts to understand the molecular basis of the development of diabetes mellitus for the treatment of this disease. At the molecular level, defects at the level of postreceptor are frequently observed in diabetic cases. Thus, insulin signaling regulators that negatively act at this level can be an attractive therapeutic target of metabolic diseases related to insulin signaling. Insulin action is propagated by extensive tyrosine phosphorylations on various insulin receptor substrates such as IRS-1. This tyrosine phosphorylated IRS-1 acts as a docking site for Src homology 2 (SH2) domain-containing proteins like the p85 regulatory subunit of type 1A phosphatidylinositol (PI) 3-kinase (PI3K), which eventually activates PI3K/Akt pathway for the control of insulin’s metabolic action (i.e. glucose uptake). Based upon the character of insulin signal transduction, I performed unbiased perturbation screening by using SH2 domain libraries and insulin-induced Akt activation is used as readout. To consolidate the relevance with diabetes, I monitored the expression changes of the screening hits in the diabetic skeletal muscle. From these combined screenings, I identified C1-Ten as a novel protein related to diabetes. C1-Ten (also known as tensin2) is a member of the tensin family, which also includes tensin1, tensin3, and cten. Except cten, the shortest form, all tensins contain a protein tyrosine phosphatase (PTPase) domain, similar to PTEN. However, tensin1 lacks a cysteine residue which is critical for a PTPase to exhibit its enzymatic activity. Because of this, tensin family is regarded as a pseudophosphatase. In this study, I demonstrated for the first time that C1-Ten is a relevant PTPase of IRS-1, negatively acting on insulin/IGF-1 signaling. Skeletal muscle accounts for ~75% of whole body glucose uptake and comprises ~40% of body mass contributing to body movement. Both glucose uptake and muscle mass are under the control of IRS-1-associated PI3K activity. Therefore, defects in IRS-1-associated PI3K activity in skeletal muscle contribute to impaired glucose metabolism and loss of muscle mass, known as muscle atrophy. That is, reduced responsiveness to insulin is mainly due to the decrease in the IRS-1-associated PI3K activity caused by a reduction of IRS-1 tyrosine phosphorylation and IRS-1 protein level itself. In this study, I observed that significant reduction of IRS-1 protein in the skeletal muscle of both type 1 and type 2 diabetes where C1-Ten levels are significantly increased. C1-Ten expression in myotubes and adult skeletal muscle induces muscle atrophy and C1-Ten depletion causes hypertrophy of myotubes, the process of which involves the activation of signaling, downstream of IRS-1 (Akt/S6K1). Also, C1-Ten inhibited glucose uptake by the muscle. More importantly, catabolic glucocorticoid that is known to be increased in the diabetic mice induces the significant increase of C1-Ten level and causes muscle atrophy. In contrast to those in catabolic muscle, C1-Ten levels decreased in anabolic muscle such as terminally differentiated myotubes and normal skeletal muscle. This suggests that C1-Ten, upregulated in diabetic muscle, is associated with muscle pathologies like muscle atrophy. Even if I and others observed dramatic decrease of IRS-1 levels in the catabolic muscle, the precise mechanism of reduced IRS-1 under a catabolic condition is unknown. Interestingly, I observed that C1-Ten induces atrophy of myotubes at the level of IRS-1. Knockdown of glucocorticoid-induced C1-Ten efficiently blocked glucocorticoid-induced atrophy of myotubes via restoration of IRS-1 level. More importantly, I identified Y612 of IRS-1, one of the most important residues for PI3K activity is regulated by C1-Ten PTPase. Tyrosine 612 dephosphorylated IRS-1 showed enhanced IRS-1 degradation. These findings suggest a novel type of IRS-1 degradation mechanism, which is dependent on C1-Ten and extends our understanding of the molecular mechanism of IRS-1 reduction under a catabolic condition, which eventually exacerbates defects in the muscle. An imbalance between anabolic and catabolic pathways due to insulin deficiency, insulin resistance, or glucocorticoid excess can lead to various catabolic diseases including diabetes mellitus. In skeletal muscle, breakdown of this balance causes muscle atrophy and reduced glucose uptake, affecting whole body homeostasis. IRS-1 reduction is commonly observed in this catabolic state. However, there is no known mediator of IRS-1 reduction for this process, which can be a key contributor of muscle malfunction. In this study, I discovered for the first time that a previously unidentified role of C1-Ten as a PTPase of IRS-1, affecting IRS-1 stability and contributing to the pathogenesis of diabetes. Also, PTPase activity-dependent involvement of C1-Ten on muscle atrophy and glucose uptake potentially proposes C1-Ten as an attractive therapeutic target for the treatment of diabetes.
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