6dlg

Structural highlights

Function

SHIP1_MOUSE Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. Acts as a negative regulator of B-cell antigen receptor signaling. Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Acts as a negative regulator of myeloid cell proliferation/survival and chemotaxis, mast cell degranulation, immune cells homeostasis, integrin alpha-IIb/beta-3 signaling in platelets and JNK signaling in B-cells. Regulates proliferation of osteoclast precursors, macrophage programming, phagocytosis and activation and is required for endotoxin tolerance. Involved in the control of cell-cell junctions, CD32a signaling in neutrophils and modulation of EGF-induced phospholipase C activity. Key regulator of neutrophil migration, by governing the formation of the leading edge and polarization required for chemotaxis. Modulates FCGR3/CD16-mediated cytotoxicity in NK cells. Mediates the activin/TGF-beta-induced apoptosis through its Smad-dependent expression. May also hydrolyze PtdIns(1,3,4,5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]}

References

1. ↑ Cox D, Dale BM, Kashiwada M, Helgason CD, Greenberg S. A regulatory role for Src homology 2 domain-containing inositol 5'-phosphatase (SHIP) in phagocytosis mediated by Fc gamma receptors and complement receptor 3 (alpha(M)beta(2); CD11b/CD18). J Exp Med. 2001 Jan 1;193(1):61-71. PMID:11136821
2. ↑ Damen JE, Ware MD, Kalesnikoff J, Hughes MR, Krystal G. SHIP's C-terminus is essential for its hydrolysis of PIP3 and inhibition of mast cell degranulation. Blood. 2001 Mar 1;97(5):1343-51. PMID:11222379
3. ↑ Malbec O, Schmitt C, Bruhns P, Krystal G, Fridman WH, Daeron M. Src homology 2 domain-containing inositol 5-phosphatase 1 mediates cell cycle arrest by FcgammaRIIB. J Biol Chem. 2001 Aug 10;276(32):30381-91. Epub 2001 May 18. PMID:11359765 doi:http://dx.doi.org/10.1074/jbc.M011094200
4. ↑ Mancini A, Koch A, Wilms R, Tamura T. The SH2-containing inositol 5-phosphatase (SHIP)-1 is implicated in the control of cell-cell junction and induces dissociation and dispersion of MDCK cells. Oncogene. 2002 Feb 28;21(10):1477-84. PMID:11896575 doi:http://dx.doi.org/10.1038/sj.onc.1205224
5. ↑ Takeshita S, Namba N, Zhao JJ, Jiang Y, Genant HK, Silva MJ, Brodt MD, Helgason CD, Kalesnikoff J, Rauh MJ, Humphries RK, Krystal G, Teitelbaum SL, Ross FP. SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts. Nat Med. 2002 Sep;8(9):943-9. Epub 2002 Aug 5. PMID:12161749 doi:http://dx.doi.org/10.1038/nm752
6. ↑ Tridandapani S, Wang Y, Marsh CB, Anderson CL. Src homology 2 domain-containing inositol polyphosphate phosphatase regulates NF-kappa B-mediated gene transcription by phagocytic Fc gamma Rs in human myeloid cells. J Immunol. 2002 Oct 15;169(8):4370-8. PMID:12370370
7. ↑ Valderrama-Carvajal H, Cocolakis E, Lacerte A, Lee EH, Krystal G, Ali S, Lebrun JJ. Activin/TGF-beta induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP. Nat Cell Biol. 2002 Dec;4(12):963-9. PMID:12447389 doi:http://dx.doi.org/10.1038/ncb885
8. ↑ Baran CP, Tridandapani S, Helgason CD, Humphries RK, Krystal G, Marsh CB. The inositol 5'-phosphatase SHIP-1 and the Src kinase Lyn negatively regulate macrophage colony-stimulating factor-induced Akt activity. J Biol Chem. 2003 Oct 3;278(40):38628-36. Epub 2003 Jul 25. PMID:12882960 doi:10.1074/jbc.M305021200
9. ↑ Robson JD, Davidson D, Veillette A. Inhibition of the Jun N-terminal protein kinase pathway by SHIP-1, a lipid phosphatase that interacts with the adaptor molecule Dok-3. Mol Cell Biol. 2004 Mar;24(6):2332-43. PMID:14993273
10. ↑ Maxwell MJ, Yuan Y, Anderson KE, Hibbs ML, Salem HH, Jackson SP. SHIP1 and Lyn Kinase Negatively Regulate Integrin alpha IIb beta 3 signaling in platelets. J Biol Chem. 2004 Jul 30;279(31):32196-204. Epub 2004 May 27. PMID:15166241 doi:http://dx.doi.org/10.1074/jbc.M400746200
11. ↑ Zhou P, Kitaura H, Teitelbaum SL, Krystal G, Ross FP, Takeshita S. SHIP1 negatively regulates proliferation of osteoclast precursors via Akt-dependent alterations in D-type cyclins and p27. J Immunol. 2006 Dec 15;177(12):8777-84. PMID:17142780
12. ↑ Nishio M, Watanabe K, Sasaki J, Taya C, Takasuga S, Iizuka R, Balla T, Yamazaki M, Watanabe H, Itoh R, Kuroda S, Horie Y, Forster I, Mak TW, Yonekawa H, Penninger JM, Kanaho Y, Suzuki A, Sasaki T. Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIP1. Nat Cell Biol. 2007 Jan;9(1):36-44. doi: 10.1038/ncb1515. Epub 2006 Dec 17. PMID:17173042 doi:http://dx.doi.org/10.1038/ncb1515
13. ↑ Lioubin MN, Algate PA, Tsai S, Carlberg K, Aebersold A, Rohrschneider LR. p150Ship, a signal transduction molecule with inositol polyphosphate-5-phosphatase activity. Genes Dev. 1996 May 1;10(9):1084-95. PMID:8654924
14. ↑ Ono M, Bolland S, Tempst P, Ravetch JV. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor Fc(gamma)RIIB. Nature. 1996 Sep 19;383(6597):263-6. PMID:8805703 doi:http://dx.doi.org/10.1038/383263a0
15. ↑ Ono M, Okada H, Bolland S, Yanagi S, Kurosaki T, Ravetch JV. Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Cell. 1997 Jul 25;90(2):293-301. PMID:9244303
16. ↑ Helgason CD, Damen JE, Rosten P, Grewal R, Sorensen P, Chappel SM, Borowski A, Jirik F, Krystal G, Humphries RK. Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span. Genes Dev. 1998 Jun 1;12(11):1610-20. PMID:9620849
17. ↑ Huber M, Helgason CD, Damen JE, Liu L, Humphries RK, Krystal G. The src homology 2-containing inositol phosphatase (SHIP) is the gatekeeper of mast cell degranulation. Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11330-5. doi:, 10.1073/pnas.95.19.11330. PMID:9736736 doi:http://dx.doi.org/10.1073/pnas.95.19.11330
18. ↑ Liu Q, Oliveira-Dos-Santos AJ, Mariathasan S, Bouchard D, Jones J, Sarao R, Kozieradzki I, Ohashi PS, Penninger JM, Dumont DJ. The inositol polyphosphate 5-phosphatase ship is a crucial negative regulator of B cell antigen receptor signaling. J Exp Med. 1998 Oct 5;188(7):1333-42. PMID:9763612
19. ↑ Huber M, Helgason CD, Scheid MP, Duronio V, Humphries RK, Krystal G. Targeted disruption of SHIP leads to Steel factor-induced degranulation of mast cells. EMBO J. 1998 Dec 15;17(24):7311-9. PMID:9857188 doi:http://dx.doi.org/10.1093/emboj/17.24.7311