Phosphoinositol phosphatase SHIP2 promotes cancer development and metastasis coupled with alterations in EGF receptor turnover

Prasad, Nagendra; Tandon, Manish; Badve, Sunil; Snyder, Paul W.; Nakshatri, Harikrishna

doi:10.1093/carcin/bgm213

Cited by 63 publications

(90 citation statements)

References 49 publications

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“…PtdIns(3,4)P 2 was demonstrated to have a higher affinity for Akt than PtdIns(3,4,5)P 3 , (14), and in accordance with this finding, several studies have shown that reduction of SHIP2 activity may result in decreased, rather then increased, Akt activity, leading to reduced proliferation and enhanced cell death (15,24). SHIP2 overexpression has been described in primary breast cancer, and SHIP2 is required for the prosurvival signal initiated by epidermal growth factor receptor in this tumor type (25). We now describe three novel pan-SHIP inhibitors, which were able to effectively kill two breast cancer cell lines in addition to three MM cell lines.…”

Section: Discussionmentioning

confidence: 56%

Therapeutic Potential of SH2 Domain-Containing Inositol-5′-Phosphatase 1 (SHIP1) and SHIP2 Inhibition in Cancer

Fuhler

Brooks

Toms

et al. 2011

Mol Med

114

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Many tumors present with increased activation of the phosphatidylinositol 3-kinase (PI3K)-PtdIns(3,4,5)P 3 -protein kinase B (PKB/Akt) signaling pathway. It has long been thought that the lipid phosphatases SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 act as tumor suppressors by counteracting with the survival signal induced by this pathway through hydrolysis or PtdIns(3,4,5)P 3 to PtdIns(3,4)P 2 . However, a growing body of evidence suggests that PtdInd(3,4)P 2 is capable of, and essential for, Akt activation, thus suggesting a potential role for SHIP1/2 enzymes as proto-oncogenes. We recently described a novel SHIP1-selective chemical inhibitor (3α-aminocholestane [3AC]) that is capable of killing malignant hematologic cells. In this study, we further investigate the biochemical consequences of 3AC treatment in multiple myeloma (MM) and demonstrate that SHIP1 inhibition arrests MM cell lines in either G0/G1 or G2/M stages of the cell cycle, leading to caspase activation and apoptosis. In addition, we show that in vivo growth of MM cells is blocked by treatment of mice with the SHIP1 inhibitor 3AC. Furthermore, we identify three novel pan-SHIP1/2 inhibitors that efficiently kill MM cells through G2/M arrest, caspase activation and apoptosis induction. Interestingly, in SHIP2-expressing breast cancer cells that lack SHIP1 expression, pan-SHIP1/2 inhibition also reduces viable cell numbers, which can be rescued by addition of exogenous PtdIns(3,4)P 2 . In conclusion, this study shows that inhibition of SHIP1 and SHIP2 may have broad clinical application in the treatment of multiple tumor types.

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Section: Discussionmentioning

confidence: 56%

Therapeutic Potential of SH2 Domain-Containing Inositol-5′-Phosphatase 1 (SHIP1) and SHIP2 Inhibition in Cancer

Fuhler

Brooks

Toms

et al. 2011

Mol Med

114

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“…Reports in the literature reveal that the function of SHIP2 as a pro-or anti-oncogene is not clear and very much depends on the cellular model Prasad et al, 2008a;Taylor et al, 2000). In breast cancer cells, where it has been mostly studied, SHIP2 participates in the mechanism of invadopodium maturation by producing the key lipid PI(3,4)P2 (Sharma et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

SHIP2 controls plasma membrane PI(4,5)P2 thereby participating in the control of cell migration in 1321 N1 glioblastoma cells

Edimo

Ghosh

Derua

et al. 2016

Journal of Cell Science

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Phosphoinositides, particularly phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], are recognized by SHIP2 (also known as INPPL1) a member of the inositol polyphosphate 5-phosphatase family. SHIP2 dephosphorylates PI(3,4,5)P3 to form PI(3,4)P2; the latter interacts with specific target proteins (e.g. lamellipodin). Although the preferred SHIP2 substrate is PI(3,4,5)P3, PI(4,5)P2 can also be dephosphorylated by this enzyme to phosphatidylinositol 4-phosphate (PI4P). Through depletion of SHIP2 in the glioblastoma cell line 1321 N1, we show that SHIP2 inhibits cell migration. In different glioblastoma cell lines and primary cultures, SHIP2 staining at the plasma membrane partly overlaps with PI(4,5)P2 immunoreactivity. PI(4,5)P2 was upregulated in SHIP2-deficient N1 cells as compared to control cells; in contrast, PI4P was very much decreased in SHIP2-deficient cells. Therefore, SHIP2 controls both PI(3,4,5)P3 and PI(4,5)P2 levels in intact cells. In 1321 N1 cells, the PI(4,5)P2-binding protein myosin-1c was identified as a new interactor of SHIP2. Regulation of PI(4,5)P2 and PI4P content by SHIP2 controls 1321 N1 cell migration through the organization of focal adhesions. Thus, our results reveal a new role of SHIP2 in the control of PI(4,5)P2, PI4P and cell migration in PTEN-deficient glioblastoma 1321 N1 cells.

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“…These two proteins, along with STAM, CBL, and the 5Ј-phosphoinositol phosphatase SHIP2 were previously identified as Y phosphorylated and part of the EGFR network (46). SHIP2 is linked to RTK signaling through its SH2 domain, is an effector of EGFR endocytosis (47), and considered a drug target in breast cancer, where its expression was linked to EGFR inhibitor sensitivity in MDA-231 cells (48). Epsin-4 interacts with clathrin and the AP-2 complex (including AP2B1 identified herein).…”

Section: Discussionmentioning

confidence: 99%

Multiple myeloma phosphotyrosine proteomic profile associated with FGFR3 expression, ligand activation, and drug inhibition

St-Germain

Taylor

Tong

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Signaling by growth factor receptor tyrosine kinases is manifest through networks of proteins that are substrates and/or bind to the activated receptors. FGF receptor-3 (FGFR3) is a drug target in a subset of human multiple myelomas (MM) and is mutationally activated in some cervical and colon and many bladder cancers and in certain skeletal dysplasias. To define the FGFR3 network in multiple myeloma, mass spectrometry was used to identify and quantify phosphotyrosine (pY) sites modulated by FGFR3 activation and inhibition in myeloma-derived KMS11 cells. Label-free quantification of peptide ion currents indicated the activation of FGFR3 by phosphorylation of tandem tyrosines in the kinase domain activation loop when cellular pY phosphatases were inhibited by pervanadate. Among the 175 proteins that accumulated pY in response to pervanadate was a subset of 52 including FGFR3 that contained a total of 61 pY sites that were sensitive to inhibition by the FGFR3 inhibitor PD173074. The FGFR3 isoform containing the tandem pY motif in its activation loop was targeted by PD173074. Forty of the drug-sensitive pY sites, including two located within the 35-residue cytoplasmic domain of the transmembrane growth factor binding proteoglycan (and multiple myeloma biomarker) Syndecan-1/CD138, were also stimulated in cells treated with the ligand FGF1, providing additional validation of their link to FGFR3. The identification of these overlapping sets of co-modulated tyrosine phosphorylations presents an outline of an FGFR3 network in the MM model and demonstrates the potential for pharmacodynamic monitoring by label-free quantitative phospho-proteomics.proteomics ͉ syndecan ͉ mass spectrometry ͉ comodulation T yrosine (Y) phosphorylation is a key mechanism of cell regulation, and tyrosine kinases are frequently activated in cancers (1). FGF receptor-3 (FGFR3) is a receptor tyrosine kinase (RTK) and drug target in a subset of human multiple myelomas (MM) that contain the t(4;14) translocation, which is responsible for the aberrant expression of FGFR3 in these tumors (2). Mutations that activate FGFR3 are prevalent in bladder cancer, have been observed in t(4;14) MM, cervical and colon cancers, and are associated with skeletal dysplasias (3). A fundamental question in MM is the nature of phosphotyrosine (pY) signaling networks in tumors that express FGFR3.RTKs such as FGFR3 function to a large extent through ligandinduced autophosphorylation, which facilitates the activation of downstream effectors (4). Autophosphorylation of FGFR1 proceeds sequentially, involving one, and then both adjacent tyrosines in the kinase domain activation loop (AL), which causes an approximately 50-fold and 1,000-fold activation of kinase activity, respectively, followed by the modification of other receptor tyrosines (5). FGFR3 also contains tandem tyrosines in its AL (6), and has four additional Y sites including pY760 and pY724, which are linked to downstream signaling effector proteins (7,8). Systematic in vitro investigations of pY-dependent prote...

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Phosphoinositol phosphatase SHIP2 promotes cancer development and metastasis coupled with alterations in EGF receptor turnover

Cited by 63 publications

References 49 publications

Therapeutic Potential of SH2 Domain-Containing Inositol-5′-Phosphatase 1 (SHIP1) and SHIP2 Inhibition in Cancer

Therapeutic Potential of SH2 Domain-Containing Inositol-5′-Phosphatase 1 (SHIP1) and SHIP2 Inhibition in Cancer

SHIP2 controls plasma membrane PI(4,5)P2 thereby participating in the control of cell migration in 1321 N1 glioblastoma cells

Multiple myeloma phosphotyrosine proteomic profile associated with FGFR3 expression, ligand activation, and drug inhibition

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