Biology:INPP5D

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1 (SHIP1) is an enzyme with phosphatase activity. SHIP1 is structured by multiple domain and is encoded by the INPP5D gene in humans.[1][2][3] SHIP1 is expressed predominantly by hematopoietic cells[4] but also, for example, by osteoblasts[5] and endothelial cells.[6] This phosphatase is important for the regulation of cellular activation. Not only catalytic but also adaptor activities of this protein are involved in this process. Its movement from the cytosol to the cytoplasmic membrane, where predominantly performs its function, is mediated by tyrosine phosphorylation of the intracellular chains of cell surface receptors that SHIP1 binds. Insufficient regulation of SHIP1 leads to different pathologies.[7]

Structure and regulation of activity

SHIP1 is a 145 kDa large protein and member of the inositol polyphosphate-5-phosphatase (INPP5) family. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[3]

At the N-terminus of the protein, SH2 domain is formed. This domain is important for the interaction of SHIP1 with the phosphorylated protein chains that SHIP1 binds. Highly conserved phosphatase domain is in central part of the protein. This catalytic domain is flanked on the N-terminal side by the PH-like domain that binds phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P3) and is overlapped on C-terminus with the C2 domain that binds phosphatidylinositol-3,4-bisphosphate (PI(4, 5)P2). The C-tail is not structured, but contains a proline-rich region that forms the motif for binding SH3 domain and also contains sequence containing tyrosine 915 (Y915) and tyrosine 1022 (Y1022) (in human cell) that is typical for interaction with the phosphotyrosine binding domain (PTB domain).

Phosphatase activity of SHIP1 can be allosteric regulated by phosphorylation of the catalytic domain on serine 440 (Ser440), this phosphorylation is mediated by cAMP-dependent protein kinase A (PKA).[8] Second allosteric regulation is mediated by binding PI(3,4)P2 to the C2 domain.[9] Furthermore, binding PDB domain to C-terminus of SHIP1 is regulated by Y915 and Y1022 phosphorylation.[10]

Function

At the plasma membrane, the protein hydrolyzes the 5' phosphate from phosphatidylinositol (3,4,5)-trisphosphate and inositol-1,3,4,5-tetrakisphosphate, thereby influence the binding of many proteins to the cytoplasmic membrane thus affecting multiple signaling pathways. To access the substrate which is located on the cytoplasmic membrane, SHIP1 move from cytosol to the plasma membrane. This movement is mediated by binding its SH2 domain to the phosphorylated intracellular chains of cell surface receptors. Binding SHIP1 to phosphorylated immunoreceptor tyrosine-based inhibition motifs (ITIM) of FcγRIIB inhibits the activation of B cells including Ca2+ influx.[11] SHIP1 can also interact with other inhibitory receptors and contribute to negative signaling.[12][13] Overall, the protein functions as a negative regulator of cell proliferation and survival. Nevertheless, SHIP1 may also bind to partially phosphorylated immunoreceptor tyrosine-based activation motifs (ITAM) of some cell surface receptors, for example T cell receptor (TCR)[14] and CD79a/b.[15] SHIP1 does not bind only to intracellular chains of cell surface receptor. Its SH2 domain may also interact with phosphorylated cytoplasmic proteins, such as SHC1[16] and DOK1.[17]

The regulation of signaling by SHIP1 is not dependent only on its catalytic activity. SHIP1 can also affect cell signaling pathways independently on its catalytic activity by serving as a bridge for other proteins thereby regulate protein-protein interactions.

Interactions

INPP5D has been shown to interact with DOK2,[18] LYN,[19] CD22,[20] Grb2,[21] CRKL,[22] CD31,[23] DOK1[18][24] and SHC1.[1][18][25][26][27]

Medicines

Poor regulation of the SHIP1 function leads to different pathologies. On the one hand, its increased activity is associated with tumorogenesis. On the other hand, its low activity leads to autoinflammatory diseases.[7] This knowledge is used in drug development. In the case of autoinflammatory diseases, there is an attempt to increase SHIP1 catalytic activity by binding the small molecule to the C2 domain. This molekule should to act as allosteric activator. Currently, some molecules are under development and tested as potential anti-inflammatory drug. AQX-1125 (Rosiptor) and AQX-MN100 are both in clinical trials.[28][29][9]

References

  1. ↑ 1.0 1.1 "The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase". Proceedings of the National Academy of Sciences of the United States of America 93 (4): 1689–93. February 1996. doi:10.1073/pnas.93.4.1689. PMID 8643691. Bibcode: 1996PNAS...93.1689D. 
  2. ↑ "Cloning and characterization of human SHIP, the 145-kD inositol 5-phosphatase that associates with SHC after cytokine stimulation". Blood 88 (8): 2833–40. October 1996. doi:10.1182/blood.V88.8.2833.bloodjournal8882833. PMID 8874179. 
  3. ↑ 3.0 3.1 "Entrez Gene: INPP5D inositol polyphosphate-5-phosphatase, 145kDa". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3635. 
  4. ↑ "The human SHIP gene is differentially expressed in cell lineages of the bone marrow and blood". Blood 89 (6): 1876–85. March 1997. doi:10.1182/blood.V89.6.1876. PMID 9058707. 
  5. ↑ "SHIP is required for a functional hematopoietic stem cell niche". Blood 113 (13): 2924–33. March 2009. doi:10.1182/blood-2008-02-138008. PMID 19074735. 
  6. ↑ "Identification of Flk-1 target genes in vasculogenesis: Pim-1 is required for endothelial and mural cell differentiation in vitro". Blood 103 (12): 4536–44. June 2004. doi:10.1182/blood-2003-11-3827. PMID 14982870. http://bloodjournal.hematologylibrary.org/content/103/12/4536.long. 
  7. ↑ 7.0 7.1 "Inhibitor and activator: dual functions for SHIP in immunity and cancer". Annals of the New York Academy of Sciences 1217 (1): 1–17. January 2011. doi:10.1111/j.1749-6632.2010.05869.x. PMID 21155837. Bibcode: 2011NYASA1217....1K. 
  8. ↑ "Regulation of the Src homology 2 domain-containing inositol 5'-phosphatase (SHIP1) by the cyclic AMP-dependent protein kinase". The Journal of Biological Chemistry 284 (30): 20070–8. July 2009. doi:10.1074/jbc.M109.016865. PMID 19494109. 
  9. ↑ 9.0 9.1 "Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells". Blood 110 (6): 1942–9. September 2007. doi:10.1182/blood-2007-03-079699. PMID 17502453. 
  10. ↑ "Shc interaction with Src homology 2 domain containing inositol phosphatase (SHIP) in vivo requires the Shc-phosphotyrosine binding domain and two specific phosphotyrosines on SHIP". The Journal of Biological Chemistry 272 (16): 10396–401. April 1997. doi:10.1074/jbc.272.16.10396. PMID 9099679. 
  11. ↑ "The SH2 domain-containing inositol 5-phosphatase SHIP1 is recruited to the intracytoplasmic domain of human FcgammaRIIB and is mandatory for negative regulation of B cell activation". Immunology Letters 104 (1–2): 156–65. April 2006. doi:10.1016/j.imlet.2005.11.027. PMID 16406061. https://hal-pasteur.archives-ouvertes.fr/pasteur-00270018/file/Isnardi_et_al._Immunol._Letters_2006.pdf. 
  12. ↑ "Association of tyrosine phosphatases SHP-1 and SHP-2, inositol 5-phosphatase SHIP with gp49B1, and chromosomal assignment of the gene". The Journal of Biological Chemistry 273 (2): 1070–4. January 1998. doi:10.1074/jbc.273.2.1070. PMID 9422771. 
  13. ↑ "Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244)". Blood 105 (12): 4722–9. June 2005. doi:10.1182/blood-2004-09-3796. PMID 15713798. 
  14. ↑ "The inositol 5'-phosphatase SHIP binds to immunoreceptor signaling motifs and responds to high affinity IgE receptor aggregation". The Journal of Biological Chemistry 271 (46): 29271–8. November 1996. doi:10.1074/jbc.271.46.29271. PMID 8910587. 
  15. ↑ "The Dok-3/Grb2 adaptor module promotes inducible association of the lipid phosphatase SHIP with the BCR in a coreceptor-independent manner". European Journal of Immunology 46 (11): 2520–2530. November 2016. doi:10.1002/eji.201646431. PMID 27550373. 
  16. ↑ "Distinct mechanisms mediate SHC association with the activated and resting B cell antigen receptor" (in fr). European Journal of Immunology 26 (8): 1960–5. August 1996. doi:10.1002/eji.1830260842. PMID 8765045. 
  17. ↑ "Dok-3, a novel adapter molecule involved in the negative regulation of immunoreceptor signaling". Molecular and Cellular Biology 20 (8): 2743–54. April 2000. doi:10.1128/mcb.20.8.2743-2754.2000. PMID 10733577. 
  18. ↑ 18.0 18.1 18.2 "The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates with the dok1 phosphoprotein in bcr-Abl transformed cells". Cellular Signalling 12 (5): 317–26. May 2000. doi:10.1016/S0898-6568(00)00073-5. PMID 10822173. 
  19. ↑ "The inositol 5'-phosphatase SHIP-1 and the Src kinase Lyn negatively regulate macrophage colony-stimulating factor-induced Akt activity". The Journal of Biological Chemistry 278 (40): 38628–36. October 2003. doi:10.1074/jbc.M305021200. PMID 12882960. 
  20. ↑ "CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux". The Journal of Biological Chemistry 275 (23): 17420–7. June 2000. doi:10.1074/jbc.M001892200. PMID 10748054. 
  21. ↑ "Multiple forms of an inositol polyphosphate 5-phosphatase form signaling complexes with Shc and Grb2". Current Biology 6 (4): 438–45. April 1996. doi:10.1016/S0960-9822(02)00511-0. PMID 8723348. 
  22. ↑ "CrkL is recruited through its SH2 domain to the erythropoietin receptor and plays a role in Lyn-mediated receptor signaling". The Journal of Biological Chemistry 276 (35): 33282–90. August 2001. doi:10.1074/jbc.M102924200. PMID 11443118. 
  23. ↑ "Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP and phospholipase C-gamma1 with PECAM-1/CD31". FEBS Letters 450 (1–2): 77–83. April 1999. doi:10.1016/S0014-5793(99)00446-9. PMID 10350061. 
  24. ↑ "Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells". Blood 96 (10): 3406–13. November 2000. doi:10.1182/blood.V96.10.3406. PMID 11071635. https://pure.eur.nl/en/publications/395fb5fc-60e3-45d7-a9b1-fc7b9cc6b4bc. 
  25. ↑ "A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP2) is constitutively tyrosine phosphorylated and associated with src homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor cells". Blood 93 (8): 2707–20. April 1999. doi:10.1182/blood.V93.8.2707. PMID 10194451. 
  26. ↑ "Protein kinase C-delta is a negative regulator of antigen-induced mast cell degranulation". Molecular and Cellular Biology 22 (12): 3970–80. June 2002. doi:10.1128/MCB.22.12.3970-3980.2002. PMID 12024011. 
  27. ↑ "p135 src homology 2 domain-containing inositol 5'-phosphatase (SHIPbeta ) isoform can substitute for p145 SHIP in fcgamma RIIB1-mediated inhibitory signaling in B cells". The Journal of Biological Chemistry 275 (39): 29960–7. September 2000. doi:10.1074/jbc.M003714200. PMID 10900203. 
  28. ↑ AdisInsight. "AQX-1125". Springer. https://adisinsight.springer.com/drugs/800033407. 
  29. ↑ World Health Organization, International Nonproprietary Names for Pharmaceutical Substances (INN): Proposed INN: List 115, https://www.who.int/medicines/publications/druginformation/LP_115.pdf 

Further reading

  • "Association of the Src homology 2 domain-containing inositol 5' phosphatase (SHIP) to releasability in human basophils". Molecular Immunology 38 (16–18): 1323–7. September 2002. doi:10.1016/S0161-5890(02)00082-2. PMID 12217402. 
  • "p150Ship, a signal transduction molecule with inositol polyphosphate-5-phosphatase activity". Genes & Development 10 (9): 1084–95. May 1996. doi:10.1101/gad.10.9.1084. PMID 8654924. 
  • "Multiple forms of an inositol polyphosphate 5-phosphatase form signaling complexes with Shc and Grb2". Current Biology 6 (4): 438–45. April 1996. doi:10.1016/S0960-9822(02)00511-0. PMID 8723348. 
  • "Cloning and expression of a human placenta inositol 1,3,4,5-tetrakisphosphate and phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase". Biochemical and Biophysical Research Communications 225 (1): 243–9. August 1996. doi:10.1006/bbrc.1996.1161. PMID 8769125. 
  • "The human SHIP gene is differentially expressed in cell lineages of the bone marrow and blood". Blood 89 (6): 1876–85. March 1997. doi:10.1182/blood.V89.6.1876. PMID 9058707. 
  • "Purification and molecular cloning of SH2- and SH3-containing inositol polyphosphate-5-phosphatase, which is involved in the signaling pathway of granulocyte-macrophage colony-stimulating factor, erythropoietin, and Bcr-Abl". Blood 89 (8): 2745–56. April 1997. doi:10.1182/blood.V89.8.2745. PMID 9108392. 
  • "Interleukin-3 induces the association of the inositol 5-phosphatase SHIP with SHP2". The Journal of Biological Chemistry 272 (17): 10998–1001. April 1997. doi:10.1074/jbc.272.17.10998. PMID 9110989. 
  • "Tyrosine phosphorylation and relocation of SHIP are integrin-mediated in thrombin-stimulated human blood platelets". The Journal of Biological Chemistry 272 (43): 26857–63. October 1997. doi:10.1074/jbc.272.43.26857. PMID 9341117. 
  • "Association of tyrosine phosphatases SHP-1 and SHP-2, inositol 5-phosphatase SHIP with gp49B1, and chromosomal assignment of the gene". The Journal of Biological Chemistry 273 (2): 1070–4. January 1998. doi:10.1074/jbc.273.2.1070. PMID 9422771. 
  • "The SH2-containing inositol polyphosphate 5-phosphatase, ship, is expressed during hematopoiesis and spermatogenesis". Blood 91 (8): 2753–9. April 1998. doi:10.1182/blood.V91.8.2753.2753_2753_2759. PMID 9531585. 
  • "p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein in Flt3 ligand-stimulated hematopoietic cells". Biochemical and Biophysical Research Communications 254 (2): 440–5. January 1999. doi:10.1006/bbrc.1998.9959. PMID 9918857. 
  • "CDw150 associates with src-homology 2-containing inositol phosphatase and modulates CD95-mediated apoptosis". Journal of Immunology 162 (10): 5719–27. May 1999. doi:10.4049/jimmunol.162.10.5719. PMID 10229804. 
  • "Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP and phospholipase C-gamma1 with PECAM-1/CD31". FEBS Letters 450 (1–2): 77–83. April 1999. doi:10.1016/S0014-5793(99)00446-9. PMID 10350061. 
  • "The SH2 inositol 5-phosphatase Ship1 is recruited in an SH2-dependent manner to the erythropoietin receptor". The Journal of Biological Chemistry 275 (6): 4398–406. February 2000. doi:10.1074/jbc.275.6.4398. PMID 10660611. 
  • "Shc associates with the IL-3 receptor beta subunit, SHIP and Gab2 following IL-3 stimulation. Contribution of Shc PTB and SH2 domains". Cellular Signalling 12 (3): 183–94. March 2000. doi:10.1016/S0898-6568(99)00088-1. PMID 10704825. 
  • "Dok-3, a novel adapter molecule involved in the negative regulation of immunoreceptor signaling". Molecular and Cellular Biology 20 (8): 2743–54. April 2000. doi:10.1128/MCB.20.8.2743-2754.2000. PMID 10733577. 
  • "CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux". The Journal of Biological Chemistry 275 (23): 17420–7. June 2000. doi:10.1074/jbc.M001892200. PMID 10748054. 
  • "The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates with the dok1 phosphoprotein in bcr-Abl transformed cells". Cellular Signalling 12 (5): 317–26. May 2000. doi:10.1016/S0898-6568(00)00073-5. PMID 10822173. 

External links

  • Overview of all the structural information available in the PDB for UniProt: Q92835 (Human Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1) at the PDBe-KB.
  • Overview of all the structural information available in the PDB for UniProt: Q9ES52 (Mouse Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1) at the PDBe-KB.



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