Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0001439
UniProt IDO15357
Primary gene name(s)INPPL1
Synonym gene name(s)SHIP2
Protein namePhosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2
Protein functionPhosphatidylinositol, PtdIns phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate, PtdIns(3,4,5P3 to produce PtdIns(3,4P2, thereby negatively regulating the PI3K, phosphoinositide 3-kinase pathways. Plays a central role in regulation of PI3K-dependent insulin signaling, although the precise molecular mechanisms and signaling pathways remain unclear. While overexpression reduces both insulin-stimulated MAP kinase and Akt activation, its absence does not affect insulin signaling or GLUT4 trafficking. Confers resistance to dietary obesity. May act by regulating AKT2, but not AKT1, phosphorylation at the plasma membrane. Part of a signaling pathway that regulates actin cytoskeleton remodeling. Required for the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation. Participates in regulation of cortical and submembraneous actin by hydrolyzing PtdIns(3,4,5P3 thereby regulating membrane ruffling, PubMed:21624956. Regulates cell adhesion and cell spreading. Required for HGF-mediated lamellipodium formation, cell scattering and spreading. Acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation. Acts as a regulator of neuritogenesis by regulating PtdIns(3,4,5P3 level and is required to form an initial protrusive pattern, and later, maintain proper neurite outgrowth. Acts as a negative regulator of the FC-gamma-RIIA receptor, FCGR2A. Mediates signaling from the FC-gamma-RIIB receptor, FCGR2B, playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Involved in EGF signaling pathway. Upon stimulation by EGF, it is recruited by EGFR and dephosphorylates PtdIns(3,4,5P3. Plays a negative role in regulating the PI3K-PKB pathway, possibly by inhibiting PKB activity. Down-regulates Fc-gamma-R-mediated phagocytosis in macrophages independently of INPP5D/SHIP1. In macrophages, down-regulates NF-kappa-B-dependent gene transcription by regulating macrophage colony-stimulating factor, M-CSF-induced signaling. May also hydrolyze PtdIns(1,3,4,5P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6. Involved in endochondral ossification. {ECO:0000269|PubMed:11349134, ECO:0000269|PubMed:11739414, ECO:0000269|PubMed:12235291, ECO:0000269|PubMed:12676785, ECO:0000269|PubMed:12690104, ECO:0000269|PubMed:15668240, ECO:0000269|PubMed:17135240, ECO:0000269|PubMed:21624956, ECO:0000269|PubMed:23273569, ECO:0000269|PubMed:9660833}.
Subcellular locationCytoplasm, cytosol. Cytoplasm, cytoskeleton. Membrane;
Peripheral membrane protein. Cell projection, filopodium. Cell projection, lamellipodium. Note=Translocates to membrane ruffles when activated, translocation is probably due to different mechanisms depending on the stimulus and cell type. Partly translocated via its SH2 domain which mediates interaction with tyrosine phosphorylated receptors such as the FC-gamma-RIIB receptor, FCGR2B. Tyrosine phosphorylation may also participate in membrane localization. Insulin specifically stimulates its redistribution from the cytosol to the plasma membrane. Recruited to the membrane following M-CSF stimulation. In activated spreading platelets, localizes with actin at filopodia, lamellipodia and the central actin ring.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: O15357
Gene Ontology
(Biological Process)
Complete annatation
actin filament organization [GO:0007015];
cell adhesion [GO:0007155];
endochondral ossification [GO:0001958];
endocytosis [GO:0006897];
glucose metabolic process [GO:0006006];
immune system process [GO:0002376];
inositol phosphate metabolic process [GO:0043647];
negative regulation of cell proliferation [GO:0008285];
negative regulation of gene expression [GO:0010629];
phosphatidylinositol biosynthetic process [GO:0006661];
phosphatidylinositol dephosphorylation [GO:0046856];
post-embryonic development [GO:0009791];
response to insulin [GO:0032868];
ruffle assembly [GO:0097178]
Gene Ontology
(Molecular Function)
Complete annatation
inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity [GO:0052659];
phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity [GO:0034485];
SH2 domain binding [GO:0042169]
Gene Ontology
(Cellular Component)
Complete annatation
cytoplasm [GO:0005737];
cytoskeleton [GO:0005856];
cytosol [GO:0005829];
filopodium [GO:0030175];
Golgi apparatus [GO:0005794];
lamellipodium [GO:0030027];
plasma membrane [GO:0005886]
Protein-protein interaction109848
Phylogenetic treeO15357
HIV replication factor status Zhou et al., Cell. Host. Microbe., 2008
Brass et al., Science, 2008
Smith et al., J. Immunol, 2010
gene status
Lu et al., J. Virol., 2011
      Folds changes 8h: unknown; Folds changes 16h: unknown; Tested: unknown;
Schoggins JW and Rice CM, Curr. Opin. Virol., 2011
      Targeted viruses: unknown
      Viral life cycle: unknown
      Mechanism related to antiviral activity: unknown
Anti-viral restriction factor Liu et al., Retrovirology, 2011
      unknown (Triplicates)

Gene Expression Profile       top

            Up-regulated;            Down-regulated

For brief introduction to each study, please go to the help page.

Gene expression during HIV latency

(1). Mohammadi et al., PLoS Pathog., 2014

Differentially expressed transcripts (Pairwise) during latency and subsequent viral reactivation using several agents - Primary CD4+ T-cell based model

DMSO: Dimethyl suloxyde (negative control) - 0.0033% final
SAHA: Vorinostat (Histone deacetylase inhibitor) - 0.5 μM
CD3: TCR Stimulation by IL-2+ antiCD3/anti-CD28 antibodies
IL7: Interleukin-7 based stimulation
DISU: Disulfiram (alcohol dehydrogenase inhibitor) - 0.5 μM
AZA: 5-azacytidine (AZA; DNA methylation inhibitor) - 1 μM
Experimental Condition Log2 Fold Change P value Adjusted P value
AZA vs. CD3-0.2680143435489950.4136892968480130.535157933404279
AZA vs. DISU0.1410164851102320.5793462443171050.954982272511679
AZA vs. IL7-0.1601551971572660.4049513840535480.999311006273513
AZA vs. SAHA0.3032956234262550.2137456056097430.581996326760701
DISU vs. CD30.3965782694241570.2747556035595210.40351383165006
DISU vs. IL7-0.3107705556973340.2192093766627630.601519639204888
DISU vs. SAHA0.1650185934026120.5739062915806470.862034045847141
DMSO vs. AZA0.07907111107804150.6368157527394581
DMSO vs. CD30.3340960296730080.2969025970296650.407166271606498
DMSO vs. DISU-0.06400594547931640.7941743729890810.97560211472989
DMSO vs. IL7-0.2317230839113820.1976882227944570.70755730008981
DMSO vs. SAHA0.2196544128440870.3511834383168080.701668513704443
HIV vs. Mock in Activation0.3408199946879990.5841702402794350.999983755607037
HIV vs. Mock in Latency0.09348345495461990.5704879111269670.999834320637052
IL7 vs. CD30.1129053139597760.7251110098673580.81472964977493
SAHA vs. CD30.5481386591962480.1223888872094880.204887861613751
SAHA vs. IL70.461010338997840.05883969949812150.204178091674651
(2). Iglesias-Ussel et al., J. Virol., 2013

Up and Downregulated transcripts during Latency (Latently infected CD4+ T cells vs Uninfected)- Primary CD4+Tcell based model
Log2 Fold Change P Value
unknown unknown

Gene expression during HIV infection and replication

(1). Imbeault et al., PloS Pathog., 2012

Transcriptomic profiling of HIV-1 infected CD4+ T cells - Primary CD4+ T cells
Experiment type Log2 Fold Change P Value Adjusted P Value
Infected vs. Mock unknown unknown unknown
Infected vs. Bystander unknown unknown unknown
(2). Lefebvre et al., J. Virol., 2011

Transcriptome analysis of T-cell line (Sup T1)
Log2 Fold Change unknown
(3). Li et al., J. Immunol., 2013

Lymphatic tissue
Acute Fold Change Acute P Value Asymt Fold Change Asypt P Value AIDS Fold Change AIDS P Value
unknown unknown unknown unknown unknown unknown
(4). Chang et al., MBio., 2011

Transcriptome analysis of T-cell line (Sup T1)

Derived from Sherrill-Mix et al., BMC Retrovirol., 2015 cross validation
Up-regulated (True) TRUE
(5). Sherrill-Mix et al., BMC Retrovirol., 2015

Deep RNA-seq analysis of primary human T cell infected with low passage HIV isolate HIV89.6 - Primary CD4+ T cell based
Test Status Log2 Fold Change P Value
OK 0.14636 0.340244
(6). Rotger et al., PLoS Pathog., 2010

Genome-wide mRNA expression of CD4+ T cells from HIV-infected patient
(Genes differentially expressed (at adjusted p<0.01) according to the empirical Bayes approach)
Log2 Fold Change P Value
unknown unknown

Proteomic/Transcriptomics studies indicating differentially expressed genes mediated by HIV

(1). Greenwood et al., Elife, 2016

Activated (CD3/CD28) Primary human CD4+ T cells infected with pNL4-3-dE-EGFP. The table shows the complete (unfiltered) TMT (tandem mass tag)-based proteomic time course dataset
6 h 24 h 48 h 72 h RTi
0.952 0.918 1.082 1.295 1.066
(2). Navare et al., Virology, 2012

SUP-T1 cell line
FC-4hpi P-value FC-8hpi P-value FC-20hpi P-value Category
unknown unknown unknown unknown unknown unknown unknown
(3). Hyrcza et al., J. Virolo., 2007

Primary human CD4+ and CD8+ T Cells
Affymetrix Prob ID Fold Change In CD8? Category
unknown unknown unknown unknown

Protein Overview       top

Drug-protein Interaction       (annotations from DrugBank)      top

not found

Protein Secondary Structure       (annotations from PDB)      top

PDB Accession Method Resolution Chain Structure Preview
2K4P NMR - A=1194-1258.
2KSO NMR - B=1200-1258.
2MK2 NMR - A=20-117.
3NR8 X-ray 2.8Å A/B=419-732.
4A9C X-ray 2.1Å A/B=419-732.

HIV-1 Interaction       (annotations from NCBI HIV-1 Interaction Database)      top

not found

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa00562 Inositol phosphate metabolism - Homo sapiens (human)
hsa04070 Phosphatidylinositol signaling system - Homo sapiens (human)
hsa04662 B cell receptor signaling pathway - Homo sapiens (human)
hsa04666 Fc gamma R-mediated phagocytosis - Homo sapiens (human)
hsa04910 Insulin signaling pathway - Homo sapiens (human)