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Review
. 2011 Jan:1217:1-17.
doi: 10.1111/j.1749-6632.2010.05869.x. Epub 2010 Dec 13.

Inhibitor and activator: dual functions for SHIP in immunity and cancer

William G Kerr  1
Affiliations
Review

Inhibitor and activator: dual functions for SHIP in immunity and cancer

William G Kerr. Ann N Y Acad Sci. 2011 Jan.

Abstract

SHIP1 is at the nexus of intracellular signaling pathways in immune cells that mediate bone marrow (BM) graft rejection, production of inflammatory and immunosuppressive cytokines, immunoregulatory cell formation, the BM niche that supports development of the immune system, and immune cancers. This review summarizes how SHIP participates in normal immune physiology or the pathologies that result when SHIP is mutated. This review also proposes that SHIP can have either inhibitory or activating roles in cell signaling that are determined by whether signaling pathways distal to PI3K are promoted by SHIP's substrate (PI(3,4,5)P(3) ) or its product (PI(3,4)P(2) ). This review also proposes the "two PIP hypothesis" that postulates that both SHIP's product and its substrate are necessary for a cancer cell to achieve and sustain a malignant state. Finally, due to the recent discovery of small molecule antagonists and agonists for SHIP, this review discusses potential therapeutic settings where chemical modulation of SHIP might be of benefit.

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Conflict of interest statement

Conflict of Interest Disclosure: The author currently serves on the Scientific Advisory Board of Aquinox Pharmaceuticals (Vancouver, BC) that is devoted to chemical modulation of SHIP1 expression for therapeutic purposes. The author is also the inventor or co-inventor on patents, both issued and pending, related to modulation of SHIP expression and activity for therapeutic purposes.

Figures

Fig. 1
Fig. 1. Enzymatic generation and hydrolysis of PI(3,4,5)P3 and PI(3,4)P2 at the plasma membrane by PI3K, PTEN, SHIP and INPP4
Fig. 2
Fig. 2. SDF1/CXCL12 expression is profoundly diminished in the spleen of SHIP-/- mice
Representative photomicrographs at of frozen sections prepared from the spleens of adult SHIP+/+ (A) and SHIP-/- mice (B) that were stained with biotinylated anti-SDF1 Ab (MAB350, R&D Systems) (A, B) or a biotinylated IgG1k control antibody (C) (MOPC-31C, Becton Dickinson). Staining by the anti-SDF1 Ab or the IgG1k control Ab was revealed by a secondary stain consisting of SA-AlexaFluor 546 (Molecular Probes) (red color). The blue stain is specific for IgD and reveals B lymphocyte areas in the spleen. The above procedures were performed and the resulting photomicrographs obtained by Dr. Katrin Moser (Deutsches Rheuma-Forschungszentrum, Berlin).
Fig. 3
Fig. 3. Dual roles for SHIP in immunity are a consequence of PI(3,4,5)P3 and PI(3,4)P2 biased distal effectors
(A) PI(3,4,5)P3 biased signaling components (Akt/Grp1/Tec kinases/DAPP) and the immune functions that SHIP can inhibit by reducing PI(3,4,5)P3 levels. (B) PI(3,4)P2 biased signaling components (Akt/Irgm1/TAPP) and the immune functions that SHIP can promote by production of PI(3,4)P2.
Fig. 4
Fig. 4. The ‘Two PIP Hypothesis’ in Cancer
Signals emanating from both PI(3,4,5)P3 and PI(3,4)P2 are necessary for the cancer cell to achieve and sustain the malignant state.
See this image and copyright information in PMC

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