| 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]
Publication Abstract from PubMed
Genome-wide association studies strongly implicate neuroinflammation in late-onset Alzheimer's disease (LOAD). Genetic risk loci for LOAD are enriched for genes expressed in microglia, but the relationship among microglial LOAD risk genes has been unclear. We found that the N-terminal SH2 domain of INPP5D, an important LOAD risk gene, directly interacted with the cell death regulator RIPK1 at p-Y383 to suppress RIPK1 kinase activation. Microglial INPP5D deficiency cell-autonomously promoted RIPK1-mediated transcriptional induction of diverse LOAD risk genes, proinflammatory cytokines, complements, and ROS mediators, as well as proinflammatory signaling mediators such as Toll-like receptors (TLRs), MyD88, Nlrp3, gasdermin D, and Zbp1. RIPK1-regulated microglial transcriptomic signatures were found in microglial subtypes implicated in human Alzheimer's disease (AD) pathogenesis. Furthermore, microglial INPP5D deficiency promoted aging-dependent RIPK1-mediated development of neuronal TDP-43 pathology, neuronal loss, and motor dysfunction in a non-cell-autonomous manner. Our data suggest that INPP5D functions as an intracellular rheostat in regulating RIPK1-mediated neuroinflammation for promoting aging-related neurodegenerative diseases, including LOAD and AD-amyotrophic lateral sclerosis comorbidity.
Repression of RIPK1 kinase by INPP5D inhibits expression of diverse proinflammatory mediators and late-onset Alzheimer's disease risk factors.,Xie X, Liu J, Liang W, Zhang Y, Gong X, Yuan S, Qi C, Huang M, Shi L, Hou M, Zhang M, Liu W, Sun W, Wu Y, Li C, Cao Z, Jing H, Qian L, Liu J, Yuan S, Wang Q, Shen Y, Liu Z, Li Y, Pan H, Zhu B, Shan B, He K, Wang W, Zou C, Li Y, Chou JJ, Yuan J Immunity. 2026 Feb 10;59(2):419-437.e11. doi: 10.1016/j.immuni.2026.01.014. Epub , 2026 Feb 2. PMID:41633359[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ 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
- ↑ 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:https://dx.doi.org/10.1074/jbc.M011094200
- ↑ 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:https://dx.doi.org/10.1038/sj.onc.1205224
- ↑ 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:https://dx.doi.org/10.1038/nm752
- ↑ 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
- ↑ 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:https://dx.doi.org/10.1038/ncb885
- ↑ 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
- ↑ 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
- ↑ 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:https://dx.doi.org/10.1074/jbc.M400746200
- ↑ 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
- ↑ 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:https://dx.doi.org/10.1038/ncb1515
- ↑ 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
- ↑ 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:https://dx.doi.org/10.1038/383263a0
- ↑ 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
- ↑ 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
- ↑ 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:https://dx.doi.org/10.1073/pnas.95.19.11330
- ↑ 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
- ↑ 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:https://dx.doi.org/10.1093/emboj/17.24.7311
- ↑ Xie X, Liu J, Liang W, Zhang Y, Gong X, Yuan S, Qi C, Huang M, Shi L, Hou M, Zhang M, Liu W, Sun W, Wu Y, Li C, Cao Z, Jing H, Qian L, Liu J, Yuan S, Wang Q, Shen Y, Liu Z, Li Y, Pan H, Zhu B, Shan B, He K, Wang W, Zou C, Li Y, Chou JJ, Yuan J. Repression of RIPK1 kinase by INPP5D inhibits expression of diverse proinflammatory mediators and late-onset Alzheimer's disease risk factors. Immunity. 2026 Feb 10;59(2):419-437.e11. PMID:41633359 doi:10.1016/j.immuni.2026.01.014
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