Glucose metabolism activation by SHIP2 inhibitors via up-regulation of GLUT1 gene in L6 myotubes

Suwa, Akira; Kurama, Takeshi; Yamamoto, Tadashi; Sawada, A; Shimokawa, Teruhiko; Aramori, Ichiro

doi:10.1016/j.ejphar.2010.06.002

Cited by 21 publications

(31 citation statements)

References 18 publications

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“…This compound was initially identified in a ligand‐based drug discovery program. It causes a dose‐dependent increase in insulin‐induced phosphorylation of PKB in L6 myotubes (Suwa et al., ; Suwa et al., ). It was reported to be SHIP2 specific as compared with SHIP1, synaptojanin, and PTEN (Suwa et al., ).…”

Section: Resultsmentioning

confidence: 99%

Fibroblasts derived from patients with opsismodysplasia display SHIP2-specific cell migration and adhesion defects

et al. 2017

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The SH2 domain containing inositol phosphatase 2 (SHIP2) dephosphorylates PI(3,4,5)P3 to generate PI(3,4)P2, a lipid involved in the control of cell migration and adhesion. The INPPL1 gene that encodes SHIP2 has been found to be mutated in several cases of opsismodysplasia (OPS), a rare autosomal recessive chondrodysplasia characterized by growth plate defects and delayed bone maturation. Reported mutations often result in premature stop codons or missense mutations in SHIP2 catalytic domain. SHIP2 biochemical properties are known from studies in cancer cells; its role in endochondral ossification is unknown. Here, we report two novel mutations in the INPPL1 gene and show that cell migration is very much decreased in fibroblasts derived from three OPS patients as compared with control individuals. In contrast, cell adhesion on fibronectin is increased in OPS fibroblasts. An inhibitory effect on migration was also observed when normal fibroblasts were incubated in the presence of a SHIP2 competitive inhibitor. We conclude that both migration and adhesion are very much disrupted in OPS-derived fibroblasts. It is suggested that signaling events linked to migration and particularly to adhesion, which are lost in OPS patients, would prevent normal endochondral ossification.

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Section: Resultsmentioning

confidence: 99%

Fibroblasts derived from patients with opsismodysplasia display SHIP2-specific cell migration and adhesion defects

et al. 2017

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“…This inhibitor was also highly selective for SHIP2, and increased Akt activation, glucose consumption and glucose uptake in L6 myotubes. Both AS1938909 and the previously identified AS1949490 increased the expression level of GLUT1 mRNA in L6 myotubes, which could contribute to the increased glucose uptake . The effects of AS1938909 in vivo were not defined.…”

Section: Ship2 Inhibitors Ameliorate Metabolic Disordersmentioning

confidence: 89%

“…The same group further identified another novel SHIP2 inhibitor, AS1938909, with an IC 50 value of 0.57 µmol/L and a Ki value of 0.44 µmol/L for human SHIP2 . This inhibitor was also highly selective for SHIP2, and increased Akt activation, glucose consumption and glucose uptake in L6 myotubes.…”

Section: Ship2 Inhibitors Ameliorate Metabolic Disordersmentioning

confidence: 93%

“…A number of inhibitors have been identified, but for most of them, no data on metabolic effects are available and some inhibit also SHIP1 (see discussion on the beneficial metabolic effects of SHIP1 inhibition in paragraph 10) . A few studies describe the effects of SHIP2 inhibition on metabolic parameters either in cells in vitro or in vivo . Interestingly, we recently identified metformin, the first‐line medication used to treat T2D, as a novel SHIP2 inhibitor .…”

Section: Ship2 Inhibitors Ameliorate Metabolic Disordersmentioning

confidence: 99%

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SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

Lehtonen

2019

Acta Physiologica

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SHIP2 (Src homology 2 domain‐containing inositol 5′‐phosphatase 2) belongs to the family of 5′‐phosphatases. It regulates the phosphoinositide 3‐kinase (PI3K)‐mediated insulin signalling cascade by dephosphorylating the 5′‐position of PtdIns(3,4,5)P3 to generate PtdIns(3,4)P2, suppressing the activity of the pathway. SHIP2 mouse models and genetic studies in human propose that increased expression or activity of SHIP2 contributes to the pathogenesis of the metabolic syndrome, hypertension and type 2 diabetes. This has raised great interest to identify SHIP2 inhibitors that could be used to design new treatments for metabolic diseases. This review summarizes the central mechanisms associated with the development of diabetic kidney disease, including the role of insulin resistance, and then moves on to describe the function of SHIP2 as a regulator of metabolism in mouse models. Finally, the identification of SHIP2 inhibitors and their effects on metabolic processes in vitro and in vivo are outlined. One of the newly identified SHIP2 inhibitors is metformin, the first‐line medication prescribed to patients with type 2 diabetes, further boosting the attraction of SHIP2 as a treatment target to ameliorate metabolic disorders.

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“…Cell viability was determined by incubation with 10% AlamarBlue reagent (Biosource International, Camarillo, CA, http://www.lifetechnologies.com) for 2 hours, followed by measurement of fluorescence with excitation at 544 nm and emission at 590 nm using a spectrophotometer (Spectramax 190, Molecular Devices, Sunnyvale, CA, http://www.moleculardevices.com/). The SHIP2‐selective competitive inhibitor (AS1938909) and JNK inhibitor II (SP600125) were obtained from Merck‐Calbiochem (San Diego, CA, http://www.merckmillipore.com). PI(3,4)P2‐diC16 was purchased from Echelon Biosciences Inc. (Salt lake city, UT, http://www.echelon-inc.com).…”

Section: Methodsmentioning

confidence: 99%

A Novel Oncogenic Role of Inositol Phosphatase SHIP2 in ER-Negative Breast Cancer Stem Cells: Involvement of JNK/Vimentin Activation

Lin

et al. 2014

Stem Cells

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Overexpression of SH2-containing-5 0 -inositol phosphatase-2 (SHIP2) correlates with poor survival in breast cancer. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here, we showed that the percentage of SHIP2 1 cells was positively correlated with that of CD24 2 CD44 1 cells in 60 breast cancer specimens. Among 20 estrogen receptor (ER)-negative samples, 17 had greater SHIP2 expression in CD24 2 CD44 1 subpopulation than the remaining subpopulation. Data mining of microarray analysis of 295 breast tumors showed a significant correlation of higher SHIP2 expression with distant metastasis. Examination of patient-derived mouse xenografts revealed that SHIP2 protein and its tyrosine 1135 phosphorylation were significantly higher in BCSCs, identified as CD24 2 CD44 1 or aldehyde dehydrogenase (ALDH 1 ), than non-BCSCs. SHIP2 silencing or inhibitor of SHIP2 phosphatase significantly decreased mammosphere-forming efficiency, ALDH 1 subpopulation in vitro and tumorigenicity of BCSCs in vivo. Overexpression of SHIP2 enhanced the expression of epithelial-mesenchymal transition markers including vimentin (VIM), which was mainly expressed in ER-negative breast cancer cells with higher level in mammospheres than monolayer culture. Ablation of c-Jun N-terminal kinase 1 (JNK1), JNK2, or VIM diminished the increased ALDH 1 population and tumorigenicity, induced by SHIP2 overexpression. BCSCs displayed greater expression of phospho-JNK than nonBCSCs and silencing of JNK suppressed SHIP2-mediated upregulation of VIM. Furthermore, SHIP2 overexpression enhanced Akt activation, but Akt inhibition failed to influence SHIP2-induced phospho-JNK/VIM upregulation. In conclusion, SHIP2 plays a key role in BCSCs of ERnegative breast cancers through activation of Akt and JNK with upregulation of VIM and may serve as a target for therapy directed at BCSCs.

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Glucose metabolism activation by SHIP2 inhibitors via up-regulation of GLUT1 gene in L6 myotubes

Cited by 21 publications

References 18 publications

Fibroblasts derived from patients with opsismodysplasia display SHIP2-specific cell migration and adhesion defects

Fibroblasts derived from patients with opsismodysplasia display SHIP2-specific cell migration and adhesion defects

SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

A Novel Oncogenic Role of Inositol Phosphatase SHIP2 in ER-Negative Breast Cancer Stem Cells: Involvement of JNK/Vimentin Activation

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