Tyrosine phosphorylation of SHIP promotes its proteasomal degradation

Rüschmann, Jens; Ho, Victor W.; Antignano, Frann; Kuroda, Etsushi; Lam, Vivian; Ibaraki, Mariko; Snyder, Kim; Kim, Connie; Flavell, Richard A.; Kawakami, Toshiaki; Sly, Laura M.; Turhan, Ali G.; Krystal, Gerald

doi:10.1016/j.exphem.2010.03.010

Cited by 40 publications

(35 citation statements)

References 36 publications

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“…However, we observed a decrease in SHIP1 protein expression in MM cells upon prolonged treatment with 3AC, suggesting that these scaffolding functions may no longer play a role. It has recently been shown that SHIP-1 is ubiquitinated and targeted for proteasomal degradation upon its phosphorylation (41). However, we did not observe a difference in IGF-1-stimulated SHIP1 phosphorylation in MM cells after pretreatment with 3AC (unpublished observations, GM Fuhler).…”

Section: Discussioncontrasting

confidence: 40%

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: Discussioncontrasting

confidence: 40%

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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“…We also showed that SHIP-1 protein level was, at least in part, regulated by proteasomal degradation. As SHIP-1 contains a Src phosphorylation site, Src-dependent tyrosine phosphorylation of SHIP-1 promotes its ubiquitinylation, possibly through its association with the E3 ubiquitin ligase c-Cbl (Ruschmann et al, 2010). In fact, our western blot analysis showed mild increase of SHIP-1 protein levels by a proteasome inhibitor.…”

Section: Discussionmentioning

confidence: 65%

Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

et al. 2012

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The myelodysplastic syndromes (MDSs) comprise a group of disorders characterized by multistage progression from cytopenias to acute myeloid leukemia (AML). They display exaggerated apoptosis in early stages, but lose this behavior during evolution to AML. The molecular basis for loss of apoptosis is unknown. To investigate this critical event, we analyzed phosphatidylinositol (PI) 3 0 kinase signaling, implicated as a critical pathway of cell survival control in epithelial and hematological malignancies. PI 3 0 kinase activates Akt through its production of 3 0 phosphoinositides. In turn, the phosphoinositides are dephosphorylated by two lipid phosphatases, PTEN and SHIP-1, in myeloid cells. We studied primary MDS-enriched bone marrow cells and bone marrow sections by western blotting, immunohistochemistry, immunocytochemistry and quantitative PCR for components of the SHIP/PTEN/PI 3 0 kinase signaling circuit. We reported constitutively activated Akt, variable levels of PTEN and uniformly decreased SHIP-1 expression in MDS progenitor cells. Overexpression of SHIP-1, but not the phosphatase-deficient form, inhibited myeloid leukemic growth. Levels of microRNA (miR)-210 and miR-155 transcripts, which target SHIP-1, were increased in CD34 þ MDS cells compared with their normal counterparts. Direct binding of miR-210 to the 3 0 untranslated region of SHIP-1 was confirmed by luciferase reporter assay. Transfection of a myeloid cell line with miR-210 resulted in loss of SHIP-1 protein expression. These data suggest that miR-155 and miR-210/SHIP-1/Akt pathways could serve as clinical biomarkers for disease progression, and that miR-155 and miR-210 might serve as novel therapeutic targets in MDS.

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“…Levels of SHIP protein increased by 1 h following MG132 treatment (Fig. 1C), similar to treatment of cells with imatinib, suggesting that SHIP downregulation by v-Abl involves proteasomal degradation in a manner similar to that recently reported for BCR/ABL (33). These findings contrast to the marked stability of SHIP isoforms in normal cells, where half-lives of approximately 10 h have been reported (7).…”

contrasting

confidence: 54%

“…In vitro studies have revealed that the kinase activity of BCR/ABL suppresses SHIP protein levels, suggesting that SHIP plays a negative role in transformation by oncogenic Abl proteins (33)(34)(35). In the current study, we investigated the regulation of SHIP by v-Abl and directly tested the role of SHIP during Ab-MLV transformation.…”

mentioning

confidence: 99%

SH2-Containing Inositol 5′-Phosphatase Inhibits Transformation of Abelson Murine Leukemia Virus

Fessler

Rosenberg

Baughn

2011

J Virol

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Tyrosine phosphorylation of SHIP promotes its proteasomal degradation

Cited by 40 publications

References 36 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

Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

SH2-Containing Inositol 5′-Phosphatase Inhibits Transformation of Abelson Murine Leukemia Virus

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