INPP5D

Last updated
INPP5D
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases INPP5D , SHIP, SHIP-1, SHIP1, SIP-145, hp51CN, p150Ship, inositol polyphosphate-5-phosphatase D
External IDs OMIM: 601582 MGI: 107357 HomoloGene: 4046 GeneCards: INPP5D
Orthologs
SpeciesHumanMouse
Entrez

3635

16331

Ensembl

ENSG00000168918
ENSG00000281614

ENSMUSG00000026288

UniProt

Q92835

Q9ES52

RefSeq (mRNA)

NM_001017915
NM_005541

NM_001110192
NM_001110193
NM_010566

RefSeq (protein)

NP_001017915
NP_005532

NP_001103662
NP_001103663
NP_034696

Location (UCSC) Chr 2: 233.06 – 233.21 Mb Chr 1: 87.55 – 87.65 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6] [7] SHIP1 is expressed predominantly by hematopoietic cells [8] but also, for example, by osteoblasts [9] and endothelial cells. [10] 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. [11]

Contents

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. [7]

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). [12] Second allosteric regulation is mediated by binding PI(3,4)P2 to the C2 domain. [13] Furthermore, binding PDB domain to C-terminus of SHIP1 is regulated by Y915 and Y1022 phosphorylation. [14]

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. [15] SHIP1 can also interact with other inhibitory receptors and contribute to negative signaling. [16] [17] 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) [18] and CD79 a/b. [19] 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 [20] and DOK1. [21]

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, [22] LYN, [23] CD22, [24] Grb2, [25] CRKL, [26] CD31, [27] DOK1 [22] [28] and SHC1. [5] [22] [29] [30] [31]

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. [11] 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. [32] [33] [13]

Related Research Articles

<span class="mw-page-title-main">Insulin receptor</span> Mammalian protein found in Homo sapiens

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis; a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.

<span class="mw-page-title-main">Phosphatidylinositol (3,4,5)-trisphosphate</span> Chemical compound

Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid that resides on the plasma membrane.

<span class="mw-page-title-main">Phosphoinositide 3-kinase</span> Class of enzymes

Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.

<span class="mw-page-title-main">Phosphatidylinositol 3,4-bisphosphate</span>

Phosphatidylinositol (3,4)-bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger. The generation of PtdIns(3,4)P2 at the plasma membrane activates a number of important cell signaling pathways.

<span class="mw-page-title-main">Erythropoietin receptor</span> Protein-coding gene in the species Homo sapiens

The erythropoietin receptor (EpoR) is a protein that in humans is encoded by the EPOR gene. EpoR is a 52kDa peptide with a single carbohydrate chain resulting in an approximately 56-57 kDa protein found on the surface of EPO responding cells. It is a member of the cytokine receptor family. EpoR pre-exists as dimers. These dimers were originally thought to be formed by extracellular domain interactions, however, it is now assumed that it is formed by interactions of the transmembrane domain and that the original structure of the extracellular interaction site was due to crystallisation conditions and does not depict the native conformation. Binding of a 30 kDa ligand erythropoietin (Epo), changes the receptor's conformational change, resulting in the autophosphorylation of Jak2 kinases that are pre-associated with the receptor. At present, the best-established function of EpoR is to promote proliferation and rescue of erythroid progenitors from apoptosis.

<span class="mw-page-title-main">GRB2</span> Protein-coding gene in the species Homo sapiens

Growth factor receptor-bound protein 2, also known as Grb2, is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene.

<span class="mw-page-title-main">PTPN11</span> Protein-coding gene in humans

Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase (PTP) Shp2.

<span class="mw-page-title-main">CD22</span> Lectin molecule

CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that prevents the overactivation of the immune system and the development of autoimmune diseases.

<span class="mw-page-title-main">Lymphocyte cytosolic protein 2</span> Protein-coding gene in the species Homo sapiens

Lymphocyte cytosolic protein 2, also known as LCP2 or SLP-76, is a signal-transducing adaptor protein expressed in T cells and myeloid cells and is important in the signaling of T-cell receptors (TCRs). As an adaptor protein, SLP-76 does not have catalytic functions, primarily binding other signaling proteins to form larger signaling complexes. It is a key component of the signaling pathways of receptors with immunoreceptor tyrosine-based activation motifs (ITAMs) such as T-cell receptors, its precursors, and receptors for the Fc regions of certain antibodies. SLP-76 is expressed in T-cells and related lymphocytes like natural killer cells.

<span class="mw-page-title-main">GAB2</span> Protein-coding gene in the species Homo sapiens

GRB2-associated-binding protein 2 also known as GAB2 is a protein that in humans is encoded by the GAB2 gene.

<span class="mw-page-title-main">Janus kinase 2</span> Non-receptor tyrosine kinase and coding gene in humans

Janus kinase 2 is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family, the GM-CSF receptor family, the gp130 receptor family, and the single chain receptors.

<span class="mw-page-title-main">PIK3R1</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol 3-kinase regulatory subunit alpha is an enzyme that in humans is encoded by the PIK3R1 gene.

<span class="mw-page-title-main">PTPN6</span> Protein-coding gene in humans

Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the PTPN6 gene.

<span class="mw-page-title-main">CBL (gene)</span> Mammalian gene

Cbl is a mammalian gene family. CBL gene, a part of the Cbl family, encodes the protein CBL which is an E3 ubiquitin-protein ligase involved in cell signalling and protein ubiquitination. Mutations to this gene have been implicated in a number of human cancers, particularly acute myeloid leukaemia.

<span class="mw-page-title-main">CRKL</span> Protein-coding gene in the species Homo sapiens

Crk-like protein is a protein that in humans is encoded by the CRKL gene.

<span class="mw-page-title-main">DOK1</span> Protein-coding gene in the species Homo sapiens

Docking protein 1 is a protein that in humans is encoded by the DOK1 gene.

<span class="mw-page-title-main">INPPL1</span> Protein-coding gene in the species Homo sapiens

SH2-domain containing Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 is an enzyme that in humans is encoded by the INPPL1 gene.

<span class="mw-page-title-main">PTPN12</span> Protein-coding gene in the species Homo sapiens

Tyrosine-protein phosphatase non-receptor type 12 is an enzyme that in humans is encoded by the PTPN12 gene.

<span class="mw-page-title-main">Signal-regulatory protein alpha</span> Protein-coding gene in the species Homo sapiens

Signal regulatory protein α (SIRPα) is a regulatory membrane glycoprotein from SIRP family expressed mainly by myeloid cells and also by stem cells or neurons.

Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase is an enzyme with systematic name 1-phosphatidyl-1D-myo-inositol-3,4,5-trisphosphate 5-phosphohydrolase, that has two isoforms: SHIP1 and SHIP2 (INPPL1).

References

  1. 1 2 3 ENSG00000281614 GRCh38: Ensembl release 89: ENSG00000168918, ENSG00000281614 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026288 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Damen JE, Liu L, Rosten P, Humphries RK, Jefferson AB, Majerus PW, Krystal G (February 1996). "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. Bibcode:1996PNAS...93.1689D. doi: 10.1073/pnas.93.4.1689 . PMC   40003 . PMID   8643691.
  6. ↑ Ware MD, Rosten P, Damen JE, Liu L, Humphries RK, Krystal G (October 1996). "Cloning and characterization of human SHIP, the 145-kD inositol 5-phosphatase that associates with SHC after cytokine stimulation". Blood. 88 (8): 2833–40. doi: 10.1182/blood.V88.8.2833.bloodjournal8882833 . PMID   8874179.
  7. 1 2 "Entrez Gene: INPP5D inositol polyphosphate-5-phosphatase, 145kDa".
  8. ↑ Geier SJ, Algate PA, Carlberg K, Flowers D, Friedman C, Trask B, Rohrschneider LR (March 1997). "The human SHIP gene is differentially expressed in cell lineages of the bone marrow and blood". Blood. 89 (6): 1876–85. doi: 10.1182/blood.V89.6.1876 . PMID   9058707.
  9. ↑ Hazen AL, Smith MJ, Desponts C, Winter O, Moser K, Kerr WG (March 2009). "SHIP is required for a functional hematopoietic stem cell niche". Blood. 113 (13): 2924–33. doi:10.1182/blood-2008-02-138008. PMC   2662639 . PMID   19074735.
  10. ↑ Zippo A, De Robertis A, Bardelli M, Galvagni F, Oliviero S (June 2004). "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. doi: 10.1182/blood-2003-11-3827 . PMID   14982870. S2CID   41934928.
  11. 1 2 Kerr WG (January 2011). "Inhibitor and activator: dual functions for SHIP in immunity and cancer". Annals of the New York Academy of Sciences. 1217 (1): 1–17. Bibcode:2011NYASA1217....1K. doi:10.1111/j.1749-6632.2010.05869.x. PMC   4515353 . PMID   21155837.
  12. ↑ Zhang J, Walk SF, Ravichandran KS, Garrison JC (July 2009). "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. doi: 10.1074/jbc.M109.016865 . PMC   2740433 . PMID   19494109.
  13. 1 2 Ong CJ, Ming-Lum A, Nodwell M, Ghanipour A, Yang L, Williams DE, Kim J, Demirjian L, Qasimi P, Ruschmann J, Cao LP, Ma K, Chung SW, Duronio V, Andersen RJ, Krystal G, Mui AL (September 2007). "Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells". Blood. 110 (6): 1942–9. doi: 10.1182/blood-2007-03-079699 . PMID   17502453.
  14. ↑ Lamkin TD, Walk SF, Liu L, Damen JE, Krystal G, Ravichandran KS (April 1997). "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. doi: 10.1074/jbc.272.16.10396 . PMID   9099679.
  15. ↑ Isnardi I, Bruhns P, Bismuth G, Fridman WH, Daëron M (April 2006). "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" (PDF). Immunology Letters. 104 (1–2): 156–65. doi:10.1016/j.imlet.2005.11.027. PMID   16406061. S2CID   27071755.
  16. ↑ Kuroiwa A, Yamashita Y, Inui M, Yuasa T, Ono M, Nagabukuro A, Matsuda Y, Takai T (January 1998). "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. doi: 10.1074/jbc.273.2.1070 . PMID   9422771.
  17. ↑ Eissmann P, Beauchamp L, Wooters J, Tilton JC, Long EO, Watzl C (June 2005). "Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244)". Blood. 105 (12): 4722–9. doi: 10.1182/blood-2004-09-3796 . PMID   15713798.
  18. ↑ Osborne MA, Zenner G, Lubinus M, Zhang X, Songyang Z, Cantley LC, Majerus P, Burn P, Kochan JP (November 1996). "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. doi: 10.1074/jbc.271.46.29271 . PMID   8910587.
  19. ↑ Manno B, Oellerich T, Schnyder T, Corso J, Lösing M, Neumann K, Urlaub H, Batista FD, Engelke M, Wienands J (November 2016). "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. doi:10.1002/eji.201646431. hdl: 11858/00-001M-0000-002C-799C-E . PMID   27550373. S2CID   5676779.
  20. ↑ D'Ambrosio D, Hippen KL, Cambier JC (August 1996). "Distinct mechanisms mediate SHC association with the activated and resting B cell antigen receptor". European Journal of Immunology (in French). 26 (8): 1960–5. doi:10.1002/eji.1830260842. PMID   8765045. S2CID   13612988.
  21. ↑ Lemay S, Davidson D, Latour S, Veillette A (April 2000). "Dok-3, a novel adapter molecule involved in the negative regulation of immunoreceptor signaling". Molecular and Cellular Biology. 20 (8): 2743–54. doi:10.1128/mcb.20.8.2743-2754.2000. PMC   85490 . PMID   10733577.
  22. 1 2 3 Dunant NM, Wisniewski D, Strife A, Clarkson B, Resh MD (May 2000). "The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates with the dok1 phosphoprotein in bcr-Abl transformed cells". Cellular Signalling. 12 (5): 317–26. doi:10.1016/S0898-6568(00)00073-5. PMID   10822173.
  23. ↑ Baran CP, Tridandapani S, Helgason CD, Humphries RK, Krystal G, Marsh CB (October 2003). "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. doi: 10.1074/jbc.M305021200 . PMID   12882960.
  24. ↑ Poe JC, Fujimoto M, Jansen PJ, Miller AS, Tedder TF (June 2000). "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. doi: 10.1074/jbc.M001892200 . PMID   10748054.
  25. ↑ Kavanaugh WM, Pot DA, Chin SM, Deuter-Reinhard M, Jefferson AB, Norris FA, Masiarz FR, Cousens LS, Majerus PW, Williams LT (April 1996). "Multiple forms of an inositol polyphosphate 5-phosphatase form signaling complexes with Shc and Grb2". Current Biology. 6 (4): 438–45. Bibcode:1996CBio....6..438K. doi: 10.1016/S0960-9822(02)00511-0 . PMID   8723348. S2CID   15858192.
  26. ↑ Arai A, Kanda E, Nosaka Y, Miyasaka N, Miura O (August 2001). "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. doi: 10.1074/jbc.M102924200 . PMID   11443118.
  27. ↑ Pumphrey NJ, Taylor V, Freeman S, Douglas MR, Bradfield PF, Young SP, Lord JM, Wakelam MJ, Bird IN, Salmon M, Buckley CD (April 1999). "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. doi: 10.1016/S0014-5793(99)00446-9 . PMID   10350061. S2CID   31471121.
  28. ↑ van Dijk TB, van Den Akker E, Amelsvoort MP, Mano H, Löwenberg B, von Lindern M (November 2000). "Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells". Blood. 96 (10): 3406–13. doi:10.1182/blood.V96.10.3406. hdl: 1765/9530 . PMID   11071635.
  29. ↑ Wisniewski D, Strife A, Swendeman S, Erdjument-Bromage H, Geromanos S, Kavanaugh WM, Tempst P, Clarkson B (April 1999). "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. doi:10.1182/blood.V93.8.2707. PMID   10194451.
  30. ↑ Leitges M, Gimborn K, Elis W, Kalesnikoff J, Hughes MR, Krystal G, Huber M (June 2002). "Protein kinase C-delta is a negative regulator of antigen-induced mast cell degranulation". Molecular and Cellular Biology. 22 (12): 3970–80. doi:10.1128/MCB.22.12.3970-3980.2002. PMC   133855 . PMID   12024011.
  31. ↑ March ME, Lucas DM, Aman MJ, Ravichandran KS (September 2000). "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. doi: 10.1074/jbc.M003714200 . PMID   10900203.
  32. ↑ AdisInsight. "AQX-1125". Springer. Archived from the original on 15 July 2016. Retrieved 20 July 2016.{{cite web}}: CS1 maint: bot: original URL status unknown (link)
  33. ↑ World Health Organization, International Nonproprietary Names for Pharmaceutical Substances (INN): Proposed INN: List 115 (PDF)

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