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{{Infobox_gene}} |
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'''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.<ref name="pmid8643691">{{cite journal | vauthors = Damen JE, Liu L, Rosten P, Humphries RK, Jefferson AB, Majerus PW, Krystal G | title = The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 4 | pages = 1689–93 | date = February 1996 | pmid = 8643691 | pmc = 40003 | doi = 10.1073/pnas.93.4.1689 }}</ref><ref name="pmid8874179">{{cite journal | vauthors = Ware MD, Rosten P, Damen JE, Liu L, Humphries RK, Krystal G | title = Cloning and characterization of human SHIP, the 145-kD inositol 5-phosphatase that associates with SHC after cytokine stimulation | journal = Blood | volume = 88 | issue = 8 | pages = 2833–40 | date = October 1996 | pmid = 8874179 | pmc = | doi = }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: INPP5D inositol polyphosphate-5-phosphatase, 145kDa| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3635| |
'''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.<ref name="pmid8643691">{{cite journal | vauthors = Damen JE, Liu L, Rosten P, Humphries RK, Jefferson AB, Majerus PW, Krystal G | title = The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 4 | pages = 1689–93 | date = February 1996 | pmid = 8643691 | pmc = 40003 | doi = 10.1073/pnas.93.4.1689 }}</ref><ref name="pmid8874179">{{cite journal | vauthors = Ware MD, Rosten P, Damen JE, Liu L, Humphries RK, Krystal G | title = Cloning and characterization of human SHIP, the 145-kD inositol 5-phosphatase that associates with SHC after cytokine stimulation | journal = Blood | volume = 88 | issue = 8 | pages = 2833–40 | date = October 1996 | pmid = 8874179 | pmc = | doi = }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: INPP5D inositol polyphosphate-5-phosphatase, 145kDa| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3635| access-date = }}</ref> SHIP1 is expressed predominantly by [[Hematopoietic cell|hematopoetic cells]]<ref>{{cite journal | vauthors = Geier SJ, Algate PA, Carlberg K, Flowers D, Friedman C, Trask B, Rohrschneider LR | title = The human SHIP gene is differentially expressedincell lineages of the bone marrow and blood | journal = Blood | volume = 89 | issue = 6 | pages = 1876–85 | date = March 1997 | pmid = 9058707 | url = http://www.bloodjournal.org/content/89/6/1876 }}</ref> but also, for example, by [[Osteoblast|osteoblasts]]<ref>{{cite journal | vauthors = Hazen AL, Smith MJ, Desponts C, Winter O, Moser K, Kerr WG | title = SHIP is required for a functional hematopoietic stem cell niche | journal = Blood | volume = 113 | issue = 13 | pages = 2924–33 | date = March 2009 | pmid = 19074735 | pmc = 2662639 | doi = 10.1182/blood-2008-02-138008 | url = http://www.bloodjournal.org/content/113/13/2924 }}</ref> and [[Endothelial cell|endotelial cells]].<ref>{{cite journal | vauthors = Zippo A,De Robertis A, Bardelli M, Galvagni F, Oliviero S | title = Identification of Flk-1 target genes in vasculogenesis: Pim-1 is required for endothelial and mural cell differentiation in vitro | journal = Blood | volume = 103 | issue = 12 | pages = 4536–44 | date = June 2004 | pmid = 14982870 | doi = 10.1182/blood-2003-11-3827 }}</ref> This phosphatase is important for the regulation of cellular activation. Not only [[Catalysis|catalytic]] but also [[Adaptor protein|adaptor]] activities of this protein are involved in this process. Its movement from the [[cytosol]] to the [[Cell membrane|cytoplasmic membrane]], where predominantly performs its function, is mediated by [[tyrosine phosphorylation]] of the intracellular chains of [[Cell surface receptor|cell surface receptors]] that SHIP1 binds. Insufficient regulation of SHIP1 leads to different [[Pathology|pathologies]].<ref>{{cite journal | vauthors = Kerr WG| title = Inhibitor and activator: dual functions for SHIP in immunity and cancer | journal = Annals of the New York Academy of Sciences | volume = 1217 | issue = 1 | pages = 1–17 | date = January 2011 | pmid = 21155837 | pmc = 4515353 | doi = 10.1111/j.1749-6632.2010.05869.x }}</ref> |
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== Structure and regulation of activity == |
== Structure and regulation of activity == |
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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)-trisphosphate|phosphatidylinositol-3,4,5-triphosphate]] (PI(3,4,5)P<sub>3</sub>) and is overlaped on C-terminus with the [[C2 domain]] that binds [[Phosphatidylinositol 3,4-bisphosphate|phosphatidylinositol-3,4-bisphosphate]] (PI(4, 5)P<sub>2</sub>). 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|phosphotyrosine binding domain]] (PTB domain). |
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)-trisphosphate|phosphatidylinositol-3,4,5-triphosphate]] (PI(3,4,5)P<sub>3</sub>) and is overlaped on C-terminus with the [[C2 domain]] that binds [[Phosphatidylinositol 3,4-bisphosphate|phosphatidylinositol-3,4-bisphosphate]] (PI(4, 5)P<sub>2</sub>). 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|phosphotyrosine binding domain]] (PTB domain). |
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Phosphatase activity of SHIP1 can be allosteric regulated by phosphorylation of the catalytic domain on [[serine]] 440 (Ser440), this phosphorylation is mediated by [[Protein kinase, AMP-activated, alpha 1|cAMP-dependent protein kinase A]] (PKA)<ref>{{ |
Phosphatase activity of SHIP1 can be allosteric regulated by phosphorylation of the catalytic domain on [[serine]] 440 (Ser440), this phosphorylation is mediated by [[Protein kinase, AMP-activated, alpha 1|cAMP-dependent protein kinase A]] (PKA).<ref>{{cite journal | vauthors = Zhang J, Walk SF, Ravichandran KS, Garrison JC | title = Regulation of the Src homology2domain-containing inositol 5'-phosphatase (SHIP1) by the cyclic AMP-dependent protein kinase | journal = The Journal of Biological Chemistry | volume = 284 | issue = 30 | pages = 20070–8 | date = July 2009 | pmid = 19494109 | doi = 10.1074/jbc.M109.016865 }}</ref> Second [[allosteric regulation]] is mediated by binding PI(3,4)P<sub>2</sub> to the C2 domain.<ref>{{cite journal | vauthors = Ong CJ, Ming-Lum A, Nodwell M, Ghanipour A, Yang L, Williams DE, KimJ, Demirjian L, Qasimi P, Ruschmann J, Cao LP, Ma K, Chung SW, Duronio V, Andersen RJ, Krystal G, Mui AL | title = Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells | journal = Blood | volume = 110 | issue = 6 | pages = 1942–9 | date = September 2007 | pmid = 17502453 | doi = 10.1182/blood-2007-03-079699 }}</ref> Furthermore, binding PDB domain to C-terminus of SHIP1 is regulated by Y915 and Y1022 phosphorylation.<ref>{{cite journal | vauthors = Lamkin TD, Walk SF, Liu L, Damen JE, Krystal G, Ravichandran KS | title = Shc interaction with Src homology2domain containing inositol phosphatase (SHIP) in vivo requires the Shc-phosphotyrosine binding domain and two specific phosphotyrosines on SHIP | journal = The Journal of Biological Chemistry | volume = 272 | issue = 16 | pages = 10396–401 | date = April 1997 | pmid = 9099679 | doi = 10.1074/jbc.272.16.10396 }}</ref> |
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== Function == |
== Function == |
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 hematopoetic cells[8] but also, for example, by osteoblasts[9] and endotelial 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]
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 overlaped 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]
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. SHIP1 can also interact with other inhibitory receptors and contribute to negative signaling. Overall, the protein functions as a negative regulator of cell proliferation and survival. Nevertheles, SHIP1 may also bind to partially phosphorylated immunoreceptor tyrosine-based activation motifs (ITAM) of some cell surface receptors, for example T cell receptor (TCR) and CD79a/b. 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 and DOK1.
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.
INPP5D has been shown to interact with DOK2,[15] LYN,[16] CD22,[17] Grb2,[18] CRKL,[19] CD31,[20] DOK1[15][21] and SHC1.[5][15][22][23][24]
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. 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.[25][26]
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