O15357 (SHIP2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2
EC=3.1.3.86

Alternative name(s):
Inositol polyphosphate phosphatase-like protein 1
Short name=INPPL-1
Protein 51C
SH2 domain-containing inositol 5'-phosphatase 2
Short name=SH2 domain-containing inositol phosphatase 2
Short name=SHIP-2

Gene names

Name:	INPPL1
Synonyms:	SHIP2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1258 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, 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(3,4,5)P3 thereby regulating membrane ruffling. 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(3,4,5)P3 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(3,4,5)P3. 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(1,3,4,5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6. Ref.6 Ref.9 Ref.10 Ref.13 Ref.15 Ref.16 Ref.21 Ref.24
Catalytic activity	1-phosphatidyl-1D-myo-inositol 3,4,5-triphosphate + H2O = 1-phosphatidyl-1D-myo-inositol 3,4-diphosphate + phosphate. Ref.6 Ref.7
Enzyme regulation	Activated upon translocation to the sites of synthesis of PtdIns(3,4,5)P3 in the membrane. Enzymatic activity is enhanced in the presence of phosphatidylserine. Ref.19
Subunit structure	Interacts with tyrosine phosphorylated form of SHC1, Interacts with EGFR. Upon stimulation by the EGF signaling pathway, it forms a complex with SHC1 and EGFR. Interacts with cytoskeletal protein SORBS3/vinexin, promoting its localization to the periphery of cells. Forms a complex with filamin (FLNA or FLNB), actin, GPIb (GP1BA or GP1BB) that regulates cortical and submembraneous actin. Interacts with c-Met/MET, when c-Met/MET is phosphorylated on 'Tyr-1356'. Interacts with p130Cas/BCAR1. Interacts with CENTD3/ARAP3 via its SAM domain. Interacts with c-Cbl/CBL and CAP/SORBS1. Interacts with activated EPHA2 receptor. Interacts with receptors FCGR2A and FCGR2B. Interacts with tyrosine kinases ABL1 and TEC. Interacts with CSF1R. Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.14 Ref.15 Ref.16 Ref.20 Ref.22 Ref.23 Ref.24
Subcellular location	Cytoplasm › 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. Ref.9 Ref.10 Ref.15
Tissue specificity	Widely expressed, most prominently in skeletal muscle, heart and brain. Present in platelets. Expressed in transformed myeloid cells and in primary macrophages, but not in peripheral blood monocytes. Ref.1 Ref.2 Ref.6 Ref.15 Ref.16
Induction	By bacterial lipopolysaccharides (LPS). Ref.16 Ref.19
Domain	The SH2 domain interacts with tyrosine phosphorylated forms of proteins such as SHC1 or FCGR2A. It also mediates the interaction with p130Cas/BCAR1. The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain By similarity.
Post-translational modification	Tyrosine phosphorylated by the members of the SRC family after exposure to a diverse array of extracellular stimuli such as insulin, growth factors such as EGF or PDGF, chemokines, integrin ligands and hypertonic and oxidative stress. May be phosphorylated upon IgG receptor FCGR2B-binding. Phosphorylated at Tyr-986 following cell attachment and spreading. Phosphorylated at Tyr-1162 following EGF signaling pathway stimulation. Phosphorylated at Thr-958 in response to PDGF. Ref.6 Ref.7 Ref.9 Ref.11 Ref.12 Ref.13 Ref.16 Ref.25
Involvement in disease	Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Note: Disease susceptibility may be associated with variations affecting the gene represented in this entry. Ref.26 Ref.28 Genetic variations in INPPL1 may be a cause of susceptibility to metabolic syndrome. Metabolic syndrome is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia is absent.
Miscellaneous	Its ability to confer resistance to dietary obesity suggests that it may serve as a possible therapeutic target in cases of type 2 diabetes and obesity.
Sequence similarities	Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase family. Contains 1 SAM (sterile alpha motif) domain. Contains 1 SH2 domain.
Sequence caution	The sequence AAA50503.1 differs from that shown. Reason: Frameshift at position 1153. The sequence AAA96658.1 differs from that shown. Reason: Frameshift at several positions.

Ontologies

Keywords
Biological process	Cell adhesion Immunity
Cellular component	Cell projection Cytoplasm Cytoskeleton Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Diabetes mellitus
Domain	SH2 domain SH3-binding
Ligand	Actin-binding
Molecular function	Hydrolase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	actin filament organization Inferred from mutant phenotype Ref.21. Source: UniProtKB brain development Inferred from electronic annotation. Source: Compara cell adhesion Traceable author statement Ref.21. Source: UniProtKB endocytosis Inferred from mutant phenotype Ref.21. Source: UniProtKB glucose metabolic process Inferred from electronic annotation. Source: Compara inositol trisphosphate metabolic process Inferred from electronic annotation. Source: Compara negative regulation of DNA replication Inferred from electronic annotation. Source: Compara negative regulation of MAP kinase activity Inferred from electronic annotation. Source: Compara negative regulation of cell proliferation Inferred from electronic annotation. Source: Compara negative regulation of gene expression Inferred from electronic annotation. Source: Compara negative regulation of insulin receptor signaling pathway Inferred from electronic annotation. Source: Compara negative regulation of insulin-like growth factor receptor signaling pathway Inferred from electronic annotation. Source: Compara negative regulation of neuron projection development Inferred from electronic annotation. Source: Compara negative regulation of platelet-derived growth factor receptor signaling pathway Inferred from electronic annotation. Source: Compara phosphatidylinositol biosynthetic process Traceable author statement. Source: Reactome phosphatidylinositol phosphorylation Inferred from electronic annotation. Source: InterPro post-embryonic development Inferred from electronic annotation. Source: Compara response to drug Inferred from electronic annotation. Source: Compara response to insulin stimulus Inferred from electronic annotation. Source: Compara ruffle assembly Inferred from electronic annotation. Source: Compara small molecule metabolic process Traceable author statement. Source: Reactome
Cellular_component	Golgi apparatus Inferred from direct assay. Source: HPA cytoskeleton Inferred from electronic annotation. Source: UniProtKB-SubCell cytosol Traceable author statement. Source: Reactome filopodium Inferred from electronic annotation. Source: UniProtKB-SubCell lamellipodium Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: Compara
Molecular_function	inositol-polyphosphate 5-phosphatase activity Inferred from electronic annotation. Source: Compara phosphatidylinositol-3,4,5-trisphosphate binding Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
BCAR1	P56945	2	EBI-1384248,EBI-702093
HID1	Q8IV36	2	EBI-1384248,EBI-743438
SORBS1	Q9BX66	5	EBI-1384248,EBI-433642

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O15357-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: O15357-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-242: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1258

1258

Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2

PRO_0000302870

Regions

Domain

21 – 117

97

SH2

Domain

1196 – 1258

63

SAM

Motif

944 – 949

6

SH3-binding

Motif

983 – 986

4

NPXY motif

Compositional bias

935 – 1105

171

Pro-rich

Amino acid modifications

Modified residue

165

1

Phosphothreonine Ref.31

Modified residue

241

1

Phosphoserine Ref.31 Ref.32

Modified residue

958

1

Phosphothreonine Ref.25

Modified residue

986

1

Phosphotyrosine; by SRC Ref.9 Ref.13

Modified residue

1135

1

Phosphotyrosine Ref.18

Modified residue

1162

1

Phosphotyrosine Ref.12

Natural variations

Alternative sequence

1 – 242

242

Missing in isoform 2.

VSP_027985

Natural variant

632

1

L → I Associated with susceptibility to NIDDM. Ref.28

VAR_034980

Natural variant

721

1

V → M. Ref.28

VAR_034981

Natural variant

982

1

N → S Associated with susceptibility to NIDDM. Ref.28

VAR_034982

Natural variant

1083

1

A → G. Ref.28
Corresponds to variant rs11548491 [ dbSNP | Ensembl ].

VAR_034983

Natural variant

1114

1

A → G. Ref.2 Ref.4 Ref.5
Corresponds to variant rs1049472 [ dbSNP | Ensembl ].

VAR_034984

Experimental info

Mutagenesis

47

1

R → G: Abolishes interaction with p130Cas/BCAR1 and its ability to induce increased adhesion. Abolishes phosphorylation upon FCGR2A clustering. Ref.11 Ref.13 Ref.16

Mutagenesis

607

1

D → A: Abolishes enzyme activity but not phosphorylation upon FCGR2A clustering. Ref.13 Ref.16

Mutagenesis

958

1

T → A: Reduces PDGF-stimulated tyrosine phosphorylation and association with SHC1. Ref.13 Ref.25

Mutagenesis

986 – 987

2

YY → FF: Inducer a strong reduction of phosphorylation upon re-plating on collagen I. Ref.13

Sequence conflict

307

1

I → M in AAA96658. Ref.1

Sequence conflict

1142

1

R → A in AAA50503. Ref.1

Sequence conflict

1142

1

R → A in AAA96658. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

1258

Helix Strand Turn

Details...

Beta strand

423 – 432

10

Helix

443 – 446

4

Beta strand

450 – 453

4

Helix

459 – 461

3

Beta strand

465 – 473

9

Helix

478 – 493

16

Beta strand

498 – 505

8

Beta strand

508 – 514

7

Helix

516 – 521

6

Beta strand

522 – 532

11

Beta strand

541 – 550

10

Beta strand

553 – 561

9

Helix

569 – 582

14

Turn

591 – 593

3

Turn

595 – 598

4

Beta strand

599 – 607

9

Beta strand

612 – 614

3

Helix

616 – 624

9

Helix

629 – 632

4

Helix

636 – 642

7

Beta strand

645 – 647

3

Beta strand

690 – 696

7

Beta strand

702 – 709

8

Beta strand

715 – 718

4

Beta strand

721 – 728

8

Helix

1202 – 1206

5

Turn

1207 – 1209

3

Helix

1211 – 1213

3

Helix

1214 – 1218

5

Turn

1219 – 1221

3

Helix

1225 – 1228

4

Helix

1233 – 1238

6

Helix

1244 – 1256

13

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 24, 2009. Version 2. Checksum: D76B5AA8ACDE8CBA	FASTA	1,258	138,599
	10 20 30 40 50 60 MASACGAPGP GGALGSQAPS WYHRDLSRAA AEELLARAGR DGSFLVRDSE SVAGAFALCV 70 80 90 100 110 120 LYQKHVHTYR ILPDGEDFLA VQTSQGVPVR RFQTLGELIG LYAQPNQGLV CALLLPVEGE 130 140 150 160 170 180 REPDPPDDRD ASDGEDEKPP LPPRSGSTSI SAPTGPSSPL PAPETPTAPA AESAPNGLST 190 200 210 220 230 240 VSHDYLKGSY GLDLEAVRGG ASHLPHLTRT LATSCRRLHS EVDKVLSGLE ILSKVFDQQS 250 260 270 280 290 300 SPMVTRLLQQ QNLPQTGEQE LESLVLKLSV LKDFLSGIQK KALKALQDMS STAPPAPQPS 310 320 330 340 350 360 TRKAKTIPVQ AFEVKLDVTL GDLTKIGKSQ KFTLSVDVEG GRLVLLRRQR DSQEDWTTFT 370 380 390 400 410 420 HDRIRQLIKS QRVQNKLGVV FEKEKDRTQR KDFIFVSARK REAFCQLLQL MKNKHSKQDE 430 440 450 460 470 480 PDMISVFIGT WNMGSVPPPK NVTSWFTSKG LGKTLDEVTV TIPHDIYVFG TQENSVGDRE 490 500 510 520 530 540 WLDLLRGGLK ELTDLDYRPI AMQSLWNIKV AVLVKPEHEN RISHVSTSSV KTGIANTLGN 550 560 570 580 590 600 KGAVGVSFMF NGTSFGFVNC HLTSGNEKTA RRNQNYLDIL RLLSLGDRQL NAFDISLRFT 610 620 630 640 650 660 HLFWFGDLNY RLDMDIQEIL NYISRKEFEP LLRVDQLNLE REKHKVFLRF SEEEISFPPT 670 680 690 700 710 720 YRYERGSRDT YAWHKQKPTG VRTNVPSWCD RILWKSYPET HIICNSYGCT DDIVTSDHSP 730 740 750 760 770 780 VFGTFEVGVT SQFISKKGLS KTSDQAYIEF ESIEAIVKTA SRTKFFIEFY STCLEEYKKS 790 800 810 820 830 840 FENDAQSSDN INFLKVQWSS RQLPTLKPIL ADIEYLQDQH LLLTVKSMDG YESYGECVVA 850 860 870 880 890 900 LKSMIGSTAQ QFLTFLSHRG EETGNIRGSM KVRVPTERLG TRERLYEWIS IDKDEAGAKS 910 920 930 940 950 960 KAPSVSRGSQ EPRSGSRKPA FTEASCPLSR LFEEPEKPPP TGRPPAPPRA APREEPLTPR 970 980 990 1000 1010 1020 LKPEGAPEPE GVAAPPPKNS FNNPAYYVLE GVPHQLLPPE PPSPARAPVP SATKNKVAIT 1030 1040 1050 1060 1070 1080 VPAPQLGHHR HPRVGEGSSS DEESGGTLPP PDFPPPPLPD SAIFLPPSLD PLPGPVVRGR 1090 1100 1110 1120 1130 1140 GGAEARGPPP PKAHPRPPLP PGPSPASTFL GEVASGDDRS CSVLQMAKTL SEVDYAPAGP 1150 1160 1170 1180 1190 1200 ARSALLPGPL ELQPPRGLPS DYGRPLSFPP PRIRESIQED LAEEAPCLQG GRASGLGEAG 1210 1220 1230 1240 1250 MSAWLRAIGL ERYEEGLVHN GWDDLEFLSD ITEEDLEEAG VQDPAHKRLL LDTLQLSK
	Isoform 2 [UniParc]. Checksum: F99D2FBEDA102C1F	FASTA	1,016	113,176
	10 20 30 40 50 60 MVTRLLQQQN LPQTGEQELE SLVLKLSVLK DFLSGIQKKA LKALQDMSST APPAPQPSTR 70 80 90 100 110 120 KAKTIPVQAF EVKLDVTLGD LTKIGKSQKF TLSVDVEGGR LVLLRRQRDS QEDWTTFTHD 130 140 150 160 170 180 RIRQLIKSQR VQNKLGVVFE KEKDRTQRKD FIFVSARKRE AFCQLLQLMK NKHSKQDEPD 190 200 210 220 230 240 MISVFIGTWN MGSVPPPKNV TSWFTSKGLG KTLDEVTVTI PHDIYVFGTQ ENSVGDREWL 250 260 270 280 290 300 DLLRGGLKEL TDLDYRPIAM QSLWNIKVAV LVKPEHENRI SHVSTSSVKT GIANTLGNKG 310 320 330 340 350 360 AVGVSFMFNG TSFGFVNCHL TSGNEKTARR NQNYLDILRL LSLGDRQLNA FDISLRFTHL 370 380 390 400 410 420 FWFGDLNYRL DMDIQEILNY ISRKEFEPLL RVDQLNLERE KHKVFLRFSE EEISFPPTYR 430 440 450 460 470 480 YERGSRDTYA WHKQKPTGVR TNVPSWCDRI LWKSYPETHI ICNSYGCTDD IVTSDHSPVF 490 500 510 520 530 540 GTFEVGVTSQ FISKKGLSKT SDQAYIEFES IEAIVKTASR TKFFIEFYST CLEEYKKSFE 550 560 570 580 590 600 NDAQSSDNIN FLKVQWSSRQ LPTLKPILAD IEYLQDQHLL LTVKSMDGYE SYGECVVALK 610 620 630 640 650 660 SMIGSTAQQF LTFLSHRGEE TGNIRGSMKV RVPTERLGTR ERLYEWISID KDEAGAKSKA 670 680 690 700 710 720 PSVSRGSQEP RSGSRKPAFT EASCPLSRLF EEPEKPPPTG RPPAPPRAAP REEPLTPRLK 730 740 750 760 770 780 PEGAPEPEGV AAPPPKNSFN NPAYYVLEGV PHQLLPPEPP SPARAPVPSA TKNKVAITVP 790 800 810 820 830 840 APQLGHHRHP RVGEGSSSDE ESGGTLPPPD FPPPPLPDSA IFLPPSLDPL PGPVVRGRGG 850 860 870 880 890 900 AEARGPPPPK AHPRPPLPPG PSPASTFLGE VASGDDRSCS VLQMAKTLSE VDYAPAGPAR 910 920 930 940 950 960 SALLPGPLEL QPPRGLPSDY GRPLSFPPPR IRESIQEDLA EEAPCLQGGR ASGLGEAGMS 970 980 990 1000 1010 AWLRAIGLER YEEGLVHNGW DDLEFLSDIT EEDLEEAGVQ DPAHKRLLLD TLQLSK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and characterization of a human cDNA (INPPL1) sharing homology with inositol polyphosphate phosphatases." Hejna J.A., Saito H., Merkens L.S., Tittle T.V., Jakobs P.M., Whitney M.A., Grompe M., Friedberg A.S., Moses R.E. Genomics 29:285-287(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), TISSUE SPECIFICITY.
[2]	"Identification of a second SH2-domain-containing protein closely related to the phosphatidylinositol polyphosphate 5-phosphatase SHIP." Pesesse X., Deleu S., De Smedt F., Drayer L., Erneux C. Biochem. Biophys. Res. Commun. 239:697-700(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, VARIANT GLY-1114. Tissue: Hippocampus.
[3]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT GLY-1114.
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT GLY-1114.
[6]	"Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein." Habib T., Hejna J.A., Moses R.E., Decker S.J. J. Biol. Chem. 273:18605-18609(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, ENZYME ACTIVITY, TISSUE SPECIFICITY, PHOSPHORYLATION, INTERACTION WITH SHC1.
[7]	"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." Wisniewski D., Strife A., Swendeman S., Erdjument-Bromage H., Geromanos S., Kavanaugh W.M., Tempst P., Clarkson B. Blood 93:2707-2720(1999) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY, ENZYME ACTIVITY, PHOSPHORYLATION, INTERACTION WITH SHC1 AND ABL1.
[8]	"Molecular basis of the recruitment of the SH2 domain-containing inositol 5-phosphatases SHIP1 and SHIP2 by fcgamma RIIB." Bruhns P., Vely F., Malbec O., Fridman W.H., Vivier E., Daeeron M. J. Biol. Chem. 275:37357-37364(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FCGR2B.
[9]	"The Src homology 2 domain containing inositol 5-phosphatase SHIP2 is recruited to the epidermal growth factor (EGF) receptor and dephosphorylates phosphatidylinositol 3,4,5-trisphosphate in EGF-stimulated COS-7 cells." Pesesse X., Dewaste V., De Smedt F., Laffargue M., Giuriato S., Moreau C., Payrastre B., Erneux C. J. Biol. Chem. 276:28348-28355(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH EGFR AND SHC1, PHOSPHORYLATION AT TYR-986.
[10]	"The SH2-containing inositol polyphosphate 5-phosphatase, SHIP-2, binds filamin and regulates submembraneous actin." Dyson J.M., O'Malley C.J., Becanovic J., Munday A.D., Berndt M.C., Coghill I.D., Nandurkar H.H., Ooms L.M., Mitchell C.A. J. Cell Biol. 155:1065-1079(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH FLNA AND FLNB.
[11]	"SH2-containing inositol 5'-phosphatase SHIP2 associates with the p130(Cas) adapter protein and regulates cellular adhesion and spreading." Prasad N., Topping R.S., Decker S.J. Mol. Cell. Biol. 21:1416-1428(2001) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION, INTERACTION WITH BCAR1, MUTAGENESIS OF ARG-47.
[12]	"Tyrosine phosphorylation mapping of the epidermal growth factor receptor signaling pathway." Steen H., Kuster B., Fernandez M., Pandey A., Mann M. J. Biol. Chem. 277:1031-1039(2002) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT TYR-1162.
[13]	"Src family tyrosine kinases regulate adhesion-dependent tyrosine phosphorylation of 5'-inositol phosphatase SHIP2 during cell attachment and spreading on collagen I." Prasad N., Topping R.S., Decker S.J. J. Cell Sci. 115:3807-3815(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT TYR-986, MUTAGENESIS OF 986-TYR-TYR-987.
[14]	"The c-Cbl-associated protein and c-Cbl are two new partners of the SH2-containing inositol polyphosphate 5-phosphatase SHIP2." Vandenbroere I., Paternotte N., Dumont J.E., Erneux C., Pirson I. Biochem. Biophys. Res. Commun. 300:494-500(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CBL AND SORBS1.
[15]	"SHIP-2 forms a tetrameric complex with filamin, actin, and GPIb-IX-V: localization of SHIP-2 to the activated platelet actin cytoskeleton." Dyson J.M., Munday A.D., Kong A.M., Huysmans R.D., Matzaris M., Layton M.J., Nandurkar H.H., Berndt M.C., Mitchell C.A. Blood 102:940-948(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INTERACTION WITH ACTIN; FILAMIN AND GPIB.
[16]	"SHIP-2 inositol phosphatase is inducibly expressed in human monocytes and serves to regulate Fcgamma receptor-mediated signaling." Pengal R.A., Ganesan L.P., Fang H., Marsh C.B., Anderson C.L., Tridandapani S. J. Biol. Chem. 278:22657-22663(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY, INDUCTION, PHOSPHORYLATION, INTERACTION WITH FCGR2A, MUTAGENESIS OF ARG-47 AND ASP-607.
[17]	"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells." Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J. Nat. Biotechnol. 23:94-101(2005) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[18]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1135, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[19]	"The influence of anionic lipids on SHIP2 phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase activity." Vandeput F., Backers K., Villeret V., Pesesse X., Erneux C. Cell. Signal. 18:2193-2199(2006) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION.
[20]	"SHIP2 interaction with the cytoskeletal protein Vinexin." Paternotte N., Zhang J., Vandenbroere I., Backers K., Blero D., Kioka N., Vanderwinden J.-M., Pirson I., Erneux C. FEBS J. 272:6052-6066(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SORBS3.
[21]	"SH2-containing 5'-inositol phosphatase, SHIP2, regulates cytoskeleton organization and ligand-dependent down-regulation of the epidermal growth factor receptor." Prasad N.K., Decker S.J. J. Biol. Chem. 280:13129-13136(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[22]	"The SH2-domian-containing inositol 5-phosphatase (SHIP)-2 binds to c-Met directly via tyrosine residue 1356 and involves hepatocyte growth factor (HGF)-induced lamellipodium formation, cell scattering and cell spreading." Koch A., Mancini A., El Bounkari O., Tamura T. Oncogene 24:3436-3447(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MET.
[23]	"The PI3K effector Arap3 interacts with the PI(3,4,5)P3 phosphatase SHIP2 in a SAM domain-dependent manner." Raaijmakers J.H., Deneubourg L., Rehmann H., de Koning J., Zhang Z., Krugmann S., Erneux C., Bos J.L. Cell. Signal. 19:1249-1257(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CENTD3.
[24]	"Regulation of EphA2 receptor endocytosis by SHIP2 lipid phosphatase via phosphatidylinositol 3-Kinase-dependent Rac1 activation." Zhuang G., Hunter S., Hwang Y., Chen J. J. Biol. Chem. 282:2683-2694(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH EPHA2.
[25]	"Regulation of PDGF-stimulated SHIP2 tyrosine phosphorylation and association with Shc in 3T3-L1 preadipocytes." Artemenko Y., Gagnon A., Ibrahim S., Sorisky A. J. Cell. Physiol. 211:598-607(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-958, MUTAGENESIS OF THR-958.
[26]	"The gene INPPL1, encoding the lipid phosphatase SHIP2, is a candidate for type 2 diabetes in rat and man." Marion E., Kaisaki P.J., Pouillon V., Gueydan C., Levy J.C., Bodson A., Krzentowski G., Daubresse J.-C., Mockel J., Behrends J., Servais G., Szpirer C., Kruys V., Gauguier D., Schurmans S. Diabetes 51:2012-2017(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN NIDDM.
[27]	"Polymorphisms in type II SH2 domain-containing inositol 5-phosphatase (INPPL1, SHIP2) are associated with physiological abnormalities of the metabolic syndrome." Kaisaki P.J., Delepine M., Woon P.Y., Sebag-Montefiore L., Wilder S.P., Menzel S., Vionnet N., Marion E., Riveline J.-P., Charpentier G., Schurmans S., Levy J.C., Lathrop M., Farrall M., Gauguier D. Diabetes 53:1900-1904(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN METABOLIC SYNDROME.
[28]	"Impact of SRC homology 2-containing inositol 5'-phosphatase 2 gene polymorphisms detected in a Japanese population on insulin signaling." Kagawa S., Sasaoka T., Yaguchi S., Ishihara H., Tsuneki H., Murakami S., Fukui K., Wada T., Kobayashi S., Kimura I., Kobayashi M. J. Clin. Endocrinol. Metab. 90:2911-2919(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN NIDDM, VARIANTS ILE-632; MET-721; SER-982 AND GLY-1083.
[29]	"Genetic association analysis of inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) variants with essential hypertension." Braga Marcano A.C., Burke B., Gungadoo J., Wallace C., Kaisaki P.J., Woon P.Y., Farrall M., Clayton D., Brown M., Dominiczak A., Connell J.M., Webster J., Lathrop M., Caulfield M., Samani N., Gauguier D., Munroe P.B. J. Med. Genet. 44:603-605(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN METABOLIC SYNDROME.
[30]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[31]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-165 AND SER-241, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[32]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-241, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[33]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L24444 mRNA. Translation: AAA50503.1. Frameshift.
L36818 mRNA. Translation: AAA96658.1. Frameshift.
Y14385 mRNA. Translation: CAA74743.1.
AP000593 Genomic DNA. No translation available.
CH471076 Genomic DNA. Translation: EAW74855.1.
BC140853 mRNA. Translation: AAI40854.1.

IPI

IPI00016932.
IPI00795687.

PIR

JC5765.

RefSeq

NP_001558.3. NM_001567.3.

UniGene

Hs.523875.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2K4P	NMR	-	A	1194-1258	[»]
2KSO	NMR	-	B	1200-1258	[»]
3NR8	X-ray	2.80	A/B	419-732	[»]
4A9C	X-ray	2.10	A/B	419-732	[»]

ProteinModelPortal

O15357.

SMR

O15357. Positions 9-186, 422-731, 1194-1258.

ModBase

Search...

Protein-protein interaction databases

IntAct

O15357. 16 interactions.

MINT

MINT-137208.

STRING

9606.ENSP00000298229.

PTM databases

PhosphoSite

O15357.

Proteomic databases

PaxDb

O15357.

PRIDE

O15357.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000298229; ENSP00000298229; ENSG00000165458.
ENST00000538751; ENSP00000444619; ENSG00000165458.
ENST00000541756; ENSP00000446360; ENSG00000165458.

GeneID

3636.

KEGG

hsa:3636.

UCSC

uc001osf.3. human.

Organism-specific databases

CTD

3636.

GeneCards

GC11P071935.

H-InvDB

HIX0201720.

HGNC

HGNC:6080. INPPL1.

HPA

HPA037601.

MIM

125853. phenotype.
600829. gene.

neXtProt

NX_O15357.

PharmGKB

PA29888.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5411.

HOGENOM

HOG000004836.

HOVERGEN

HBG106726.

InParanoid

O15357.

KO

K15909.

OMA

YQKHVHT.

OrthoDB

EOG4GMTW4.

PhylomeDB

O15357.

Enzyme and pathway databases

BioCyc

MetaCyc:HS09233-MONOMER.

Pathway_Interaction_DB

pi3kcipathway. Class I PI3K signaling events.
epha2_fwdpathway. EPHA2 forward signaling.
met_pathway. Signaling events activated by Hepatocyte Growth Factor Receptor (c-Met).

Reactome

REACT_111217. Metabolism.
REACT_6900. Immune System.

SABIO-RK

O15357.

Gene expression databases

ArrayExpress

O15357.

Bgee

O15357.

CleanEx

HS_INPPL1.

Genevestigator

O15357.

Family and domain databases

Gene3D

1.10.150.50. 1 hit.
3.30.505.10. 1 hit.

InterPro

IPR005135. Endo/exonuclease/phosphatase.
IPR000300. IPPc.
IPR001660. SAM.
IPR013761. SAM/pointed.
IPR011510. SAM_2.
IPR000980. SH2.
[Graphical view]

Pfam

PF03372. Exo_endo_phos. 1 hit.
PF07647. SAM_2. 1 hit.
PF00017. SH2. 1 hit.
[Graphical view]

PRINTS

PR00401. SH2DOMAIN.

SMART

SM00128. IPPc. 1 hit.
SM00454. SAM. 1 hit.
SM00252. SH2. 1 hit.
[Graphical view]

SUPFAM

SSF56219. Exo_endo_phos. 1 hit.
SSF47769. SAM_homology. 1 hit.

PROSITE

PS50105. SAM_DOMAIN. 1 hit.
PS50001. SH2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

INPPL1. human.

EvolutionaryTrace

O15357.

GenomeRNAi

3636.

NextBio

14233.

SOURCE

Search...

Entry information

Entry name

SHIP2_HUMAN

Accession

Primary (citable) accession number: O15357
Secondary accession number(s): B2RTX5, Q13577, Q13578

Entry history

Integrated into UniProtKB/Swiss-Prot:	September 11, 2007
Last sequence update:	November 24, 2009
Last modified:	May 1, 2013
This is version 95 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.