Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance

Abstract

IRTKS encodes a member of the IRSp53/MIM homology domain family, which has been shown to play an important role in the formation of plasma membrane protrusions. Although the phosphorylation of IRTKS occurs in response to insulin stimulation, the role of this protein in insulin signaling remains unknown. Here we show that IRTKS-deficient mice exhibit insulin resistance, including hyperglycemia, hyperinsulinemia, glucose intolerance, decreased insulin sensitivity, and increased hepatic glucose production. The administration of ectopic IRTKS can ameliorate the insulin resistance of IRTKS-deficient and diabetic mice. In parallel, the expression level of IRTKS was significantly decreased in diabetic mouse model. Furthermore, DNA hypermethylation of the IRTKS promoter was also observed in these subjects. We also show that IRTKS, as an adaptor of the insulin receptor (IR), modulates IR-IRS1-PI3K-AKT signaling via regulating the phosphorylation of IR. These findings add new insights into our understanding of insulin signaling and resistance.

Redundant functions of I-BAR family members, IRSp53 and IRTKS, are essential for embryonic development

“…Consistent with previous reports, IRTKS − / − mice did not exhibit developmental problems and were phenotypically normal (data not shown)34. To examine whether IRTKS acts redundantly with IRSp53 during embryogenesis, we generated mice heterozygous for IRSp53 in the IRTKS null background, and analysed embryonic litters from IRSp53 +/− ;IRTKS − / − intercrosses (Fig.…”

“…For instance, MIM was shown to be dispensable for embryonic development but is required for maintaining the integrity of kidney epithelia intercellular junctions, B-cell development, and glutamatergic synaptic transmission363738. In addition, we, in this study, and others have found that IRTKS deficient mice, while defective in insulin regulation, exhibit no developmental defects34. To date, IRSp53 is the only I-BAR member shown to exhibit altered Mendalian ratios at birth when deleted in mice; however, its role during embryonic development was not investigated2224.…”

IRTKS is correlated with progression and survival time of patients with gastric cancer

“…To understand the impact of IRTKS on the role of p53 in tumour suppression in vivo, we further crossed IRTKS- knockout mice7 with genetically inactivated p53 mice to generate various mouse genotypes. Among them, we monitored and observed six groups: p53 +/+ IRTKS +/+ , p53 +/+ IRTKS − /− , p53 +/− IRTKS +/+ , p53 +/− IRTKS − /− , p53 − /− IRTKS +/+ and p53 − /− IRTKS − /− .…”

“…IRTKS -knockout mice were previously generated and were housed in Shanghai Model Organisms Center 7. Heterozygous IRTKS mice were mated with heterozygous p53 mice (Jackson Laboratory) to generate IRTKS +/− p53 +/−  mice.…”

The SH3 domain distinguishes the role of I-BAR proteins IRTKS and MIM in chemotactic response to serum

“…In addition, IRTKS is implicated in plasma membrane dynamics and actin bundling associated with cell shape changes, migration and proliferation [5]. Mice with depletion of the IRTKS gene showed insulin resistance symptoms such as glucose intolerance, hyperglycemia, insulin less-sensitivity, hyperinsulinemia, and excessive production of hepatic glucose [13]. Furthermore, IRTKS suppresses innate immune responses against RNA virus through the Rig-IMAVs signaling pathway, thereby down-regulating extravagant inflammation [14].…”