Lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation

Hoekstra, Elmer; Das, Asha; Willemsen, Marcella; Swets, Marloes; Kuppen, Peter J.K.; Woude, C. Janneke van der; Bruno, Marco J.; Shah, Jigisha P.; Hagen, Timo L.M. ten; Chisholm, John D.; Kerr, William G.; Peppelenbosch, Maikel P.; Fuhler, Gwenny M.

doi:10.18632/oncotarget.12321

Cited by 51 publications

(49 citation statements)

References 53 publications

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“…Inhibitors identified in virtual screening included Food and Drug Administration-approved drugs used to treat cardiovascular disease, certain types of cancer, autoimmune diseases, anorexia, cachexia, and weight loss associated with cancer and AIDS (1,(48)(49)(50). Emerging evidence indicates that in addition to regulating insulin signaling, cytoskeleton remodeling, and receptor endocytosis (51), SHIP2 is implicated in the development and progression of certain types of cancer (52). This, together with our in silico data, confirms the importance of SHIP2 as a drug target for diabetes and specific types of cancer.…”

Section: Discussionsupporting

confidence: 83%

“…Emerging evidence indicates that in addition to regulating insulin signaling, cytoskeleton remodeling, and receptor endocytosis (51), SHIP2 is implicated in the development and progression of certain types of cancer (52). This, together with our in silico data, confirms the importance of SHIP2 as a drug target for diabetes and specific types of cancer.…”

Section: Discussionmentioning

confidence: 99%

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Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

Polianskyte-Prause¹,

Tolvanen²,

Lindfors³

et al. 2018

FASEB j.

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Metformin, the first-line drug to treat type 2 diabetes (T2D), inhibits mitochondrial glycerolphosphate dehydrogenase in the liver to suppress gluconeogenesis. However, the direct target and the underlying mechanisms by which metformin increases glucose uptake in peripheral tissues remain uncharacterized. Lipid phosphatase Src homology 2 domain-containing inositol-5-phosphatase 2 (SHIP2) is upregulated in diabetic rodent models and suppresses insulin signaling by reducing Akt activation, leading to insulin resistance and diminished glucose uptake. Here, we demonstrate that metformin directly binds to and reduces the catalytic activity of the recombinant SHIP2 phosphatase domain in vitro. Metformin inhibits SHIP2 in cultured cells and in skeletal muscle and kidney of db/db mice. In SHIP2-overexpressing myotubes, metformin ameliorates reduced glucose uptake by slowing down glucose transporter 4 endocytosis. SHIP2 overexpression reduces Akt activity and enhances podocyte apoptosis, and both are restored to normal levels by metformin. SHIP2 activity is elevated in glomeruli of patients with T2D receiving nonmetformin medication, but not in patients receiving metformin, compared with people without diabetes. Furthermore, podocyte loss in kidneys of metformin-treated T2D patients is reduced compared with patients receiving nonmetformin medication. Our data unravel a novel molecular mechanism by which metformin enhances glucose uptake and acts renoprotectively by reducing SHIP2 activity.—Polianskyte-Prause, Z., Tolvanen, T. A., Lindfors, S., Dumont, V., Van, M., Wang, H., Dash, S. N., Berg, M., Naams, J.-B., Hautala, L. C., Nisen, H., Mirtti, T., Groop, P.-H., Wähälä, K., Tienari, J., Lehtonen, S. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

Polianskyte-Prause¹,

Tolvanen²,

Lindfors³

et al. 2018

FASEB j.

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“…The in vitro and in vivo studies described above, revealing that SHIP2 overexpression suppresses insulin signalling and debilitates glucose metabolism, have increased the interest to develop SHIP2 inhibitors as a potential therapeutic approach to treat obesity‐induced insulin resistance and T2D. 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 .…”

Section: Ship2 Inhibitors Ameliorate Metabolic Disordersmentioning

confidence: 99%

“…In line with this “two PIP hypothesis”, studies revealing SHIP2 as a target to treat cancer and showing beneficial effects of SHIP2 inhibitors are emerging. In clinical specimens of breast, colorectal, non‐small cell lung and hepatocellular cancer, the expression level of SHIP2 has been shown to be elevated and to correlate with decreased patient survival. Beneficial effects of SHIP2 inhibition have been proposed in breast and colorectal cancer .…”

Section: Benefits and Caveats Of Inhibiting Ship2mentioning

confidence: 99%

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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“…SHIP2 has role in signaling after activation of hematopoietic growth factor receptors leading to its phosphorylation and SHC1 association (Wisniewski et al 1999;Srivastava, Sudan, and Kerr 2013). Depending on the cellular context, SHIP2 can either be anti or pro-oncogenic (Taylor et al 2000;Hoekstra et al 2016), however its role in CML has not been established. SHIP2 is constitutively phosphorylated in both primary CML cells and p210 expressing cells (Odai et al 1997;Wisniewski et al 1999).…”

Section: Resultsmentioning

confidence: 99%

Elucidation of protein-protein interactions necessary for maintenance of the BCR-ABL signaling complex

Gregor

Bosakova

Niţă

et al. 2019

Preprint

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Approximately 50% of chronic myeloid leukemia (CML) patients in deep remission experience a return of clinical CML after withdrawal of tyrosine kinase inhibitors (TKIs). This suggests signaling of inactive BCR-ABL, which allows for survival of cancer cells, leading to relapse. Understanding the dynamics of BCR-ABL signaling complex holds a key to the mechanism of BCR-ABL signaling. Here, we demonstrate that TKIs inhibit catalytic activity of BCR-ABL, but do not dissolve the BCR-ABL core signaling complex consisting of CrkL, SHC1, Grb2, SOS1, cCbl, and SHIP2. We show that CrkL binds to proline-rich regions located in C-terminal, intrinsically disordered region of BCR-ABL, that deletion of pleckstrin homology domain of BCR-ABL diminishes interaction with SHC1, and that BCR-ABL sequence motif located in disordered region around phosphorylated tyrosine 177 mediates binding of at least three core complex members, the Grb2, SOS1 and cCbl. Introduction of Y177F substitution blocks association with Grb2, SOS1 and cCbl. Further, we identified SHIP2 binding sites within the src-homology and tyrosine kinase domains of BCR-ABL. We found that BCR-ABL is unable to phosphorylate SHC1 in cells lacking SHIP2. Reintroducing SHIP2 into Ship2 knock-out cells restored SHC1 phosphorylation, which depended on inositol phosphatase activity of SHIP2. Our findings provide characterization of proteinprotein interactions in the BCR-ABL signaling complex, and support the concept of targeting BCR-ABL signaling in CML by inhibition of its interactions with the members of the core complex. Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the t(9;22)(q34;q11) translocation. This translocation generates a fusion oncogene containing part of the breakpoint cluster region (

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Lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation

Cited by 51 publications

References 53 publications

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

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

Elucidation of protein-protein interactions necessary for maintenance of the BCR-ABL signaling complex

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