Disease relevance of INPP5D

• The functional role of SHIP-1 in the modulation of CD16-induced cytotoxicity was explored in NK cells infected with recombinant vaccinia viruses encoding wild-type or catalytic domain-deleted mutant SHIP-1 [1].
• We also show that PTEN and/or SHIP-1, which are PIP3 inositol phosphatases that inhibit the activation of downstream effectors of the PI3-kinase cascade, are disrupted in both ATLL neoplasias and in multilobulated nuclei-forming Jurkat cells [2].
• Indeed Lyn-deficient mice are hyper-responsive to myeloid growth factors and develop a myeloproliferative disorder that predisposes the mice to macrophage tumours, with loss of negative regulation through SHP-1 and SHIP-1 thought to be the major contributing factor to this phenotype [3].
• RESULTS: Analyses of lung histopathology and bronchoalveolar lavage cellularity revealed that the majority of SHIP-1(-/-) mice had progressive and severe pulmonary inflammation of macrophages, lymphocytes, neutrophils, and eosinophils; mucous hyperplasia; airway epithelial hypertrophy; and subepithelial fibrosis [4].
• We also apply this method to two other cases, Diffuse large B-cell lymphoma data (Shipp et al., 2002), and data of Ramaswamy et al. on multiclass diagnosis of 14 common tumor types [5].

High impact information on INPP5D

• A major player in negative regulation of FcR signaling is the inositol 5-phosphatase SHIP1 [6].
• T cell receptor for antigen induces linker for activation of T cell-dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2 [7].
• Genetic inactivation of SHIP1 led to severe defects in neutrophil polarization and motility [8].
• They also demonstrate that SHIP1, rather than phosphatase and tensin homologue (PTEN), is responsible for the degradation and localization of this lipid in neutrophils and shed light on the role of PtdIns(3,4,5)P(3) in directional sensing [9].
• Control of cell polarity and motility by the PtdIns(3,4,5)P(3) phosphatase SHIP1 [8].

Biological context of INPP5D

• CD32a cross-linking also induced the tyrosine phosphorylation of SHIP1, its translocation to the plasma membrane and its co-immunoprecipitation with CD32a [10].
• This effect was not seen when NK cells were infected with a SHIP1 mutant containing an inactive catalytic domain [11].
• These data demonstrate that CD16 engagement on NK cells induces membrane targeting and activation of SHIP-1, which acts as negative regulator of ADCC function [1].
• Fluorescence in situ hybridization, using the full-length hSHIP cDNA as a probe, mapped hSHIP to the long arm of chromosome 2 at the border between 2q36 and 2q37 [12].
• Recent studies have revealed that phagocytosis initiated by Fc gamma RIIa is tightly controlled by the inositol phosphatase SHIP-1, and the protein-tyrosine phosphatase SHP-1 [13].

Anatomical context of INPP5D

• Whereas only few lamellipodia are observed in MDCK cells 2 min after stimulation with HGF, both SHIP-2- and SHIP-1-overexpressing cells form large, broad lamellipodia [14].
• The Src Homology 2-Containing Inositol 5-Phosphatase 1 (SHIP1) is involved in CD32a signaling in human neutrophils [10].
• Differential expression of SHIP1 in CD56bright and CD56dim NK cells provides a molecular basis for distinct functional responses to monokine costimulation [11].
• Northern blot analysis suggests that human SHIP (hSHIP) is expressed as a 5.3-kb mRNA in human bone marrow and a wide variety of other tissues [12].
• This study provides the first evidence that SHIP-1 can influence the constitutive levels of PI(3,4,5)P(3) and the activity of downstream phosphoinositide 3-kinase effectors in T lymphocytes [15].

Associations of INPP5D with chemical compounds

• Neither the specific activity of SHIP1 as an inositol phosphate 5-phosphatase nor the subcellular localization of SHIP1 appeared to be altered by tyrosine phosphorylation [16].
• Conversely, the Y-2 isoleucine that determines the in vitro binding of SHP-1 and SHP-2 affected neither the binding nor the recruitment of SHIP1 or SHIP2 [17].
• Specifically, SHIP1-dependent PtdIns(3,4,5)P(3) metabolism down-regulates the stability of integrin alpha(IIb)beta(3)-fibrinogen adhesive bonds, leading to a decrease in the proportion of platelets forming shear-resistant adhesion contacts [18].
• Furthermore, the number of mast cells significantly increased, and many of these cells were undergoing degranulation, which was correlated with increased content and spontaneous release of histamine in the lung tissue of SHIP-1(-/-) mice [4].
• Distribution of polychlorinated dibenzo-p-dioxins and dibenzofurans in suspended sediments, dissolved phase and bottom sediment in the Houston Ship Channel [19].

Physical interactions of INPP5D

• However, the Dok1/SHIP1 complex was only detected in the cytosolic fraction of Bcr-Abl transformed hematopoietic cells [16].
• Preliminary binding studies using lysates from p210(bcr/abl)-expressing cells indicate that both Ptyr SHIP2 and Ptyr SHIP1 bind to the PTB domain of SHC but not to its SH2 domain [20].

Enzymatic interactions of INPP5D

• SHIP1 is a 5' inositol phosphatase that dephosphorylates the phosphatidylinositol-3 kinase (PI-3K) product PI3,4,5P3 [11].

Regulatory relationships of INPP5D

• EPO activates the tyrosine phosphorylation of Ship1, resulting in the interdependent recruitment of Shc and Grb2 [21].

Other interactions of INPP5D

• The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates with the dok1 phosphoprotein in bcr-Abl transformed cells [16].
• 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 [22].
• We examined whether the lack of expression of SHIP-1 and PTEN is shared by other leukemic T cell lines and PBLs [15].
• By using an independent approach, expression cloning, we found that the Grb2 SH3 domains bind specifically to SIP-110, a 110 kDa splice variant of SIP-145 and SIP-130, which lacks the SH2 domain [23].
• Interestingly, SHIP2 was found to selectively bind to the SH3 domain of ABL, whereas SHIP1 selectively binds to the SH3 domain of Src [20].

Analytical, diagnostic and therapeutic context of INPP5D

• As evaluated by confocal microscopy, CD16 engagement by reverse antibody-dependent cellular cytotoxicity (ADCC) rapidly induces SHIP-1 redistribution toward the area of NK cell contact with target cells and its codistribution with aggregated rafts where CD16 receptor also colocalizes [1].
• Molecular cloning and chromosomal localization in human and mouse of the SH2-containing inositol phosphatase, INPP5D (SHIP). Amgen EST Program [24].
• We next used this predictor to discover these subgroups within a second set of DLBCL biopsies that had been profiled by using oligonucleotide microarrays [Shipp, M. A., et al. (2002) Nat. Med. 8, 68-74] [25].
• We also showed that Jurkat cells expressing SHIP-1 are more resistant to H2O2-induced apoptosis than the parental cells, suggesting that SHIP-1 has an important role in leukemic cell responses to ROS in terms of signal transduction pathways and apoptosis resistance, which can be of interest in improving ROS-mediated chemotherapies [26].
• In this particular case, the otolaryngologist should always be the "Captain of the Ship." With him, as paramedical advisors and assistors, are the audiologist and the hearing aid dispenser [27].

References