CPLM 1.0 - Compendium of Protein Lysine Modification
TagContent
CPLM ID CPLM-000436
UniProt Accession
Genbank Protein ID
Genbank Nucleotide ID
Protein Name
 Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 
Protein Synonyms/Alias
 Inositol polyphosphate phosphatase-like protein 1; INPPL-1; Protein 51C; SH2 domain-containing inositol 5'-phosphatase 2; SH2 domain-containing inositol phosphatase 2; SHIP-2 
Gene Name
 INPPL1 
Gene Synonyms/Alias
 SHIP2 
Created Date
 July 27, 2013 
Organism
 Homo sapiens (Human) 
NCBI Taxa ID
 9606 
Lysine Modification
Position
Peptide
Type
References
224RLHSEVDKVLSGLEIubiquitination[1, 2]
234SGLEILSKVFDQQSSubiquitination[1, 2, 3]
267ELESLVLKLSVLKDFubiquitination[4]
315PVQAFEVKLDVTLGDubiquitination[2]
331TKIGKSQKFTLSVDVubiquitination[5]
376KSQRVQNKLGVVFEKubiquitination[3]
412CQLLQLMKNKHSKQDubiquitination[6]
779TCLEEYKKSFENDAQubiquitination[3]
Reference
 [1] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [2] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
 [3] Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass.
 Povlsen LK, Beli P, Wagner SA, Poulsen SL, Sylvestersen KB, Poulsen JW, Nielsen ML, Bekker-Jensen S, Mailand N, Choudhary C.
 Nat Cell Biol. 2012 Oct;14(10):1089-98. [PMID: 23000965]
 [4] Proteome-wide identification of ubiquitylation sites by conjugation of engineered lysine-less ubiquitin.
 Oshikawa K, Matsumoto M, Oyamada K, Nakayama KI.
 J Proteome Res. 2012 Feb 3;11(2):796-807. [PMID: 22053931]
 [5] Mass spectrometric analysis of lysine ubiquitylation reveals promiscuity at site level.
 Danielsen JM, Sylvestersen KB, Bekker-Jensen S, Szklarczyk D, Poulsen JW, Horn H, Jensen LJ, Mailand N, Nielsen ML.
 Mol Cell Proteomics. 2011 Mar;10(3):M110.003590. [PMID: 21139048]
 [6] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983] 
Functional Description
 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. Involved in endochondral ossification. 
Sequence Annotation
 DOMAIN 21 117 SH2.
 DOMAIN 1196 1258 SAM.
 MOTIF 944 949 SH3-binding.
 MOTIF 983 986 NPXY motif.
 MOD_RES 165 165 Phosphothreonine.
 MOD_RES 241 241 Phosphoserine.
 MOD_RES 958 958 Phosphothreonine.
 MOD_RES 986 986 Phosphotyrosine; by SRC.
 MOD_RES 1135 1135 Phosphotyrosine.
 MOD_RES 1162 1162 Phosphotyrosine.  
Keyword
 3D-structure; Actin-binding; Alternative splicing; Cell adhesion; Cell projection; Complete proteome; Cytoplasm; Cytoskeleton; Diabetes mellitus; Disease mutation; Hydrolase; Immunity; Membrane; Phosphoprotein; Polymorphism; Reference proteome; SH2 domain; SH3-binding. 
Sequence Source
 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 
Protein Length
 1258 AA 
Protein Sequence
MASACGAPGP GGALGSQAPS WYHRDLSRAA AEELLARAGR DGSFLVRDSE SVAGAFALCV 60
LYQKHVHTYR ILPDGEDFLA VQTSQGVPVR RFQTLGELIG LYAQPNQGLV CALLLPVEGE 120
REPDPPDDRD ASDGEDEKPP LPPRSGSTSI SAPTGPSSPL PAPETPTAPA AESAPNGLST 180
VSHDYLKGSY GLDLEAVRGG ASHLPHLTRT LATSCRRLHS EVDKVLSGLE ILSKVFDQQS 240
SPMVTRLLQQ QNLPQTGEQE LESLVLKLSV LKDFLSGIQK KALKALQDMS STAPPAPQPS 300
TRKAKTIPVQ AFEVKLDVTL GDLTKIGKSQ KFTLSVDVEG GRLVLLRRQR DSQEDWTTFT 360
HDRIRQLIKS QRVQNKLGVV FEKEKDRTQR KDFIFVSARK REAFCQLLQL MKNKHSKQDE 420
PDMISVFIGT WNMGSVPPPK NVTSWFTSKG LGKTLDEVTV TIPHDIYVFG TQENSVGDRE 480
WLDLLRGGLK ELTDLDYRPI AMQSLWNIKV AVLVKPEHEN RISHVSTSSV KTGIANTLGN 540
KGAVGVSFMF NGTSFGFVNC HLTSGNEKTA RRNQNYLDIL RLLSLGDRQL NAFDISLRFT 600
HLFWFGDLNY RLDMDIQEIL NYISRKEFEP LLRVDQLNLE REKHKVFLRF SEEEISFPPT 660
YRYERGSRDT YAWHKQKPTG VRTNVPSWCD RILWKSYPET HIICNSYGCT DDIVTSDHSP 720
VFGTFEVGVT SQFISKKGLS KTSDQAYIEF ESIEAIVKTA SRTKFFIEFY STCLEEYKKS 780
FENDAQSSDN INFLKVQWSS RQLPTLKPIL ADIEYLQDQH LLLTVKSMDG YESYGECVVA 840
LKSMIGSTAQ QFLTFLSHRG EETGNIRGSM KVRVPTERLG TRERLYEWIS IDKDEAGAKS 900
KAPSVSRGSQ EPRSGSRKPA FTEASCPLSR LFEEPEKPPP TGRPPAPPRA APREEPLTPR 960
LKPEGAPEPE GVAAPPPKNS FNNPAYYVLE GVPHQLLPPE PPSPARAPVP SATKNKVAIT 1020
VPAPQLGHHR HPRVGEGSSS DEESGGTLPP PDFPPPPLPD SAIFLPPSLD PLPGPVVRGR 1080
GGAEARGPPP PKAHPRPPLP PGPSPASTFL GEVASGDDRS CSVLQMAKTL SEVDYAPAGP 1140
ARSALLPGPL ELQPPRGLPS DYGRPLSFPP PRIRESIQED LAEEAPCLQG GRASGLGEAG 1200
MSAWLRAIGL ERYEEGLVHN GWDDLEFLSD ITEEDLEEAG VQDPAHKRLL LDTLQLSK 1258 
Gene Ontology
 GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0030175; C:filopodium; IEA:UniProtKB-SubCell.
 GO:0005794; C:Golgi apparatus; IDA:HPA.
 GO:0030027; C:lamellipodium; IEA:UniProtKB-SubCell.
 GO:0005886; C:plasma membrane; IEA:Compara.
 GO:0004445; F:inositol-polyphosphate 5-phosphatase activity; IEA:Compara.
 GO:0005547; F:phosphatidylinositol-3,4,5-trisphosphate binding; IEA:Compara.
 GO:0007015; P:actin filament organization; IMP:UniProtKB.
 GO:0007420; P:brain development; IEA:Compara.
 GO:0007155; P:cell adhesion; TAS:UniProtKB.
 GO:0006897; P:endocytosis; IMP:UniProtKB.
 GO:0006006; P:glucose metabolic process; IEA:Compara.
 GO:0043647; P:inositol phosphate metabolic process; TAS:Reactome.
 GO:0032957; P:inositol trisphosphate metabolic process; IEA:Compara.
 GO:0008285; P:negative regulation of cell proliferation; IEA:Compara.
 GO:0008156; P:negative regulation of DNA replication; IEA:Compara.
 GO:0010629; P:negative regulation of gene expression; IEA:Compara.
 GO:0046627; P:negative regulation of insulin receptor signaling pathway; IEA:Compara.
 GO:0043569; P:negative regulation of insulin-like growth factor receptor signaling pathway; IEA:Compara.
 GO:0043407; P:negative regulation of MAP kinase activity; IEA:Compara.
 GO:0010977; P:negative regulation of neuron projection development; IEA:Compara.
 GO:0010642; P:negative regulation of platelet-derived growth factor receptor signaling pathway; IEA:Compara.
 GO:0006661; P:phosphatidylinositol biosynthetic process; TAS:Reactome.
 GO:0046856; P:phosphatidylinositol dephosphorylation; IEA:InterPro.
 GO:0009791; P:post-embryonic development; IEA:Compara.
 GO:0042493; P:response to drug; IEA:Compara.
 GO:0032868; P:response to insulin stimulus; IEA:Compara.
 GO:0097178; P:ruffle assembly; IEA:Compara. 
Interpro
 IPR005135; Endo/exonuclease/phosphatase.
 IPR000300; IPPc.
 IPR001660; SAM.
 IPR013761; SAM/pointed.
 IPR011510; SAM_2.
 IPR000980; SH2. 
Pfam
 PF03372; Exo_endo_phos
 PF07647; SAM_2
 PF00017; SH2 
SMART
 SM00128; IPPc
 SM00454; SAM
 SM00252; SH2 
PROSITE
 PS50105; SAM_DOMAIN
 PS50001; SH2 
PRINTS
 PR00401; SH2DOMAIN.