Regulation of Insulin Signaling by the Phosphatidylinositol 3,4,5-Triphosphate Phosphatase SKIP through the Scaffolding Function of Pak1

Ijuin, Takeshi; Takenawa, Tadaomi

doi:10.1128/mcb.00636-12

Cited by 31 publications

(34 citation statements)

References 36 publications

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“…Among the main canonical ER stress transducers, ATF6 and the IRE1-XBP1 system are likely to be essential for the expression of the genes involved in lipid biosynthesis and protein folding, including GRP78. Our previous results have shown that an accumulation of SKIP at the plasma membrane contributes to the suppression of insulin signaling and glucose uptake; membrane-localized SKIP interacts with an active Pak1, leading to the hydrolysis of PIP 3 bound to Akt2 and PDK1 (3). Accumulation of SKIP in proximity to these PIP 3 effectors might mediate an effective inhibition of insulin signaling under ER-stressed conditions.…”

Section: Resultsmentioning

confidence: 97%

“…Akt2 phosphorylation at Thr-309 and Ser-474 was measured as described previously (3). Cell lysates were immunoprecipitated with Akt2 antibody for 1 h at 4°C, and immunoprecipitates were washed with wash buffer containing 20 mM Tris-HCl (pH 7.4), 150 mM NaCl, 50 mM NaF, 1 mM Na 3 VO 4 , and 1 mM PMSF 5 times before they were analyzed by Western blotting using antibodies for phospho-Akt (Thr-308) or phospho-Akt (Ser-473).…”

Section: Fig 1 Continuedmentioning

confidence: 99%

“…n type 2 diabetes mellitus, insulin resistance is characterized by an impairment of glucose uptake in skeletal muscle (1)(2)(3). Skeletal muscle insulin resistance is considered to be an initial metabolic defect in the development of this disease (4,5).…”

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confidence: 99%

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Phosphatidylinositol 3,4,5-Trisphosphate Phosphatase SKIP Links Endoplasmic Reticulum Stress in Skeletal Muscle to Insulin Resistance

Ijuin

Hosooka

Takenawa

2016

Molecular and Cellular Biology

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cInsulin resistance is critical in the pathogenesis of type 2 diabetes. Endoplasmic reticulum (ER) stress in liver and adipose tissues plays an important role in the development of insulin resistance. Although skeletal muscle is a primary site for insulin-dependent glucose disposal, it is unclear if ER stress in those tissues contributes to insulin resistance. In this study, we show that skeletal muscle kidney-enriched inositol polyphosphate phosphatase (SKIP), a PIP 3 (phosphatidylinositol-3,4,5-trisphosphate) phosphatase, links ER stress to insulin resistance in skeletal muscle. SKIP expression was increased due to ER stress and was higher in the skeletal muscle isolated from high-fat-diet-fed mice and db/db mice than in that from wild-type mice. Mechanistically, ER stress promotes activating transcription factor 6 (ATF6) and X-box binding protein 1 (XBP1)-dependent expression of SKIP. These findings underscore the specific and prominent role of SKIP in the development of insulin resistance in skeletal muscle.

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Section: Resultsmentioning

confidence: 97%

Section: Fig 1 Continuedmentioning

confidence: 99%

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Phosphatidylinositol 3,4,5-Trisphosphate Phosphatase SKIP Links Endoplasmic Reticulum Stress in Skeletal Muscle to Insulin Resistance

Ijuin

Hosooka

Takenawa

2016

Molecular and Cellular Biology

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“…Initially, we have shown that PAK1 is essential to whole-body glucose homeostasis given its unique role in both pancreatic β-cells and skeletal muscle 19 . Recent work by others also highlighted the importance of PAK1 in insulin secretion 39 and insulin signaling 40 . Consistent with a special requirement for PAK1 in insulin signaling, mRNA levels of PAK1 are significantly reduced in soleus and gastrocnemius skeletal muscle from obese diabetes-susceptible mice 41 .…”

Section: Discussionmentioning

confidence: 93%

Depletion of PAK1 enhances Ubiquitin-mediated Survivin degradation in pancreatic β-cells

Chen

Fueger

Wang

2013

Islets

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Functional β-cell mass deficiency in diabetes results from imbalanced β-cell death and replication, and decreased PAK1 protein levels in human islets from donors with type 2 diabetes implicates a possible role for PAK1 in maintaining β-cell mass. Here, we aim to address the linkage between PAK1 and Survivin, a protein essential for β-cell replication. PAK1 knockout (KO) mouse islets exhibited decreased expression of Survivin protein. MIN6 β-cells with siRNA-mediated suppression of PAK1 also had decreased Survivin protein and exhibited an increased level of ubiquitinated-Survivin. However, no significant changes in Survivin mRNA were found in islets from PAK1 KO mice and PAK1-depleted MIN6 β-cells. The decreased Survivin level in MIN6 cells subjected to hyperglycemic stress was prevented by expression of exogenous PAK1. Moreover, overexpressing Survivin restored proliferation of β-cells that was impaired by the loss of PAK1. These data implicate a role for PAK1 in regulating Survivin protein stability in the β-cell and suggest PAK1 as a potential molecular target for the restoration of β-cell mass.

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“…However, other metabolic tissues such as liver, brown fat and brain were not examined and may contribute to the phenotype [77]. Interestingly, SKIP inhibits insulin-induced Akt signalling via complex formation with the scaffolding protein Pak1, to promote PtdIns(3,4,5)P 3 degradation and disassociation of the PDK1-Akt complex [78]. Therefore, this data suggest SKIPmediated PtdIns(3,4,5)P 3 hydrolysis controls insulin-induced Akt signalling that may not be significantly affected by increased PtdIns(3,4)P 2 signals.…”

Section: Skip a 5-phosphatase That Regulates Metabolic Akt Signallingmentioning

confidence: 99%

Regulation of PtdIns(3,4,5)P3/Akt signalling by inositol polyphosphate 5-phosphatases

Eramo

Mitchell

2016

Biochemical Society Transactions

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The phosphoinositide 3-kinase (PI3K) generated lipid signals, PtdIns(3,4,5)P3 and PtdIns(3,4)P2, are both required for the maximal activation of the serine/threonine kinase proto-oncogene Akt. The inositol polyphosphate 5-phosphatases (5-phosphatases) hydrolyse the 5-position phosphate from the inositol head group of PtdIns(3,4,5)P3 to yield PtdIns(3,4)P2. Extensive work has revealed several 5-phosphatases inhibit PI3K-driven Akt signalling, by decreasing PtdIns(3,4,5)P3 despite increasing cellular levels of PtdIns(3,4)P2. The roles that 5-phosphatases play in suppressing cell proliferation and transformation are slow to emerge; however, the 5-phosphatase PIPP [proline-rich inositol polyphosphate 5-phosphatase; inositol polyphosphate 5-phosphatase (INPP5J)] has recently been identified as a putative tumour suppressor in melanoma and breast cancer and SHIP1 [SH2 (Src homology 2)-containing inositol phosphatase 1] inhibits haematopoietic cell proliferation. INPP5E regulates cilia stability and INPP5E mutations have been implicated ciliopathy syndromes. This review will examine 5-phosphatase regulation of PI3K/Akt signalling, focussing on the role PtdIns(3,4,5)P3 5-phosphatases play in developmental diseases and cancer.

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Regulation of Insulin Signaling by the Phosphatidylinositol 3,4,5-Triphosphate Phosphatase SKIP through the Scaffolding Function of Pak1

Cited by 31 publications

References 36 publications

Phosphatidylinositol 3,4,5-Trisphosphate Phosphatase SKIP Links Endoplasmic Reticulum Stress in Skeletal Muscle to Insulin Resistance

Phosphatidylinositol 3,4,5-Trisphosphate Phosphatase SKIP Links Endoplasmic Reticulum Stress in Skeletal Muscle to Insulin Resistance

Depletion of PAK1 enhances Ubiquitin-mediated Survivin degradation in pancreatic β-cells

Regulation of PtdIns(3,4,5)P3/Akt signalling by inositol polyphosphate 5-phosphatases

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