SKICH domain; The SKICH domains of SKIP and PIPP mediate plasma membrane localization. The functions of the SKICH domains of NDP52 and CALCOCO1 are not known.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799 231 VTLNPEGEWS-AEHDVLINYSAVPEFPSSAWDWIGLFKVTFRHVNDYVTYSWVEDDEISSNKGGKQVYMSAAEIP-DAGG 308
Cdd:pfam17751   1 VVFQNVGEWYpPDEDIECSYTLTPDFTPSSWDWIGLFKVGWKSVNDYVTYVWAKDDEVEGSNSVRQVLFKASYLPkEPEG 80

                          90       100
                  ....*....|....*....|...
gi 1728920799 309 EFLLCFYSnNLQSIVGISQPFQI 331
Cdd:pfam17751  81 FYQFCYVS-NLGSVVGISTPFQF 102

Inositol polyphosphate phosphatase, catalytic domain homologues; Mg(2+)-dependent/Li(+)-sensitive enzymes.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799   12 RELRLHLVTWNVGTASPPP-DVSSLL-QLDSLGPTM--DMYVIGLQEVNSKI--TNFLSDLAFDDPWSIFFMTVLSPLG- 84
Cdd:smart00128   1 RDIKVLIGTWNVGGLESPKvDVTSWLfQKIEVKQSEkpDIYVIGLQEVVGLApgVILETIAGKERLWSDLLESSLNGDGq 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799   85 YIKLSSVRMQGLLLLIFVKHVHLPFIRDLHTQFTRTGLYGYWGNKGGVTIRMSLYGHTVCFMNCHLPAHMENTEQRLDDF 164
Cdd:smart00128  81 YNVLAKVYLVGILVLVFVKANHLVYIKDVETFTVKTGMGGLWGNKGAVAVRFKLSDTSFCFVNSHLAAGASNVEQRNQDY 160

                          170       180       190       200       210       220
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  165 EKIL-EMQFEGENIPSALEHDVLFWFGDLNFRIADYGIHFVRESINNKRYNLLWEKDQLK 223
Cdd:smart00128 161 KTILrALSFPERALLSQFDHDVVFWFGDLNFRLDSPSYEEVRRKISKKEFDDLLEKDQLN 220

Phosphatidylinositol 5-phosphate phosphatase [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  12 RELRLHLVTWNVGTASPPPDVSSLLQLDSLG-PTMDMYVIGLQE-VNSKITNFLSDLAFD--DPWSIFFMTVLSPLG--- 84
Cdd:COG5411    28 KDVSIFVSTFNPPGKPPKASTKRWLFPEIEAtELADLYVVGLQEvVELTPGSILSADPYDrlRIWESKVLDCLNGAQsde 107

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  85 -YIKLSSVRMQGLLLLIFVKHVHLPFIRDLHTQFTRTGLYGYWGNKGGVTIRMSLYGHTVCFMNCHLPAHMENTEQRLDD 163
Cdd:COG5411   108 kYSLLRSPQLGGILLRVFSLATNLPVVKPVSGTVKKTGFGGSSSNKGAVAIRFNYERTSFCFVNSHLAAGVNNIEERIFD 187

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1728920799 164 FEKI-LEMQFE-GENIPsalEHDVLFWFGDLNFRIADYGIHFVRESINNKRYNL-LWEKDQL 222
Cdd:COG5411   188 YRSIaSNICFSrGLRIY---DHDTIFWLGDLNYRVTSTNEEVRPEIASDDGRLDkLFEYDQL 246

Inositol polyphosphate phosphatase, catalytic domain homologues; Mg(2+)-dependent/Li(+)-sensitive enzymes.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799   12 RELRLHLVTWNVGTASPPP-DVSSLL-QLDSLGPTM--DMYVIGLQEVNSKI--TNFLSDLAFDDPWSIFFMTVLSPLG- 84
Cdd:smart00128   1 RDIKVLIGTWNVGGLESPKvDVTSWLfQKIEVKQSEkpDIYVIGLQEVVGLApgVILETIAGKERLWSDLLESSLNGDGq 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799   85 YIKLSSVRMQGLLLLIFVKHVHLPFIRDLHTQFTRTGLYGYWGNKGGVTIRMSLYGHTVCFMNCHLPAHMENTEQRLDDF 164
Cdd:smart00128  81 YNVLAKVYLVGILVLVFVKANHLVYIKDVETFTVKTGMGGLWGNKGAVAVRFKLSDTSFCFVNSHLAAGASNVEQRNQDY 160

                          170       180       190       200       210       220
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  165 EKIL-EMQFEGENIPSALEHDVLFWFGDLNFRIADYGIHFVRESINNKRYNLLWEKDQLK 223
Cdd:smart00128 161 KTILrALSFPERALLSQFDHDVVFWFGDLNFRLDSPSYEEVRRKISKKEFDDLLEKDQLN 220

Catalytic inositol polyphosphate 5-phosphatase (INPP5c) domain of Type II inositol polyphosphate 5-phosphatase I, Oculocerebrorenal syndrome of Lowe 1, and related proteins; This subfamily contains the INPP5c domain of type II inositol polyphosphate 5-phosphatase I (INPP5B), Oculocerebrorenal syndrome of Lowe 1 (OCRL-1), and related proteins. It belongs to a family of Mg2+-dependent inositol polyphosphate 5-phosphatases, which hydrolyze the 5-phosphate from the inositol ring of various 5-position phosphorylated phosphoinositides (PIs) and inositol phosphates (IPs), and to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. INPP5B and OCRL1 preferentially hydrolyze the 5-phosphate of phosphatidylinositol (4,5)- bisphosphate [PI(4,5)P2] and phosphatidylinositol (3,4,5)- trisphosphate [PI(3,4,5)P3]. INPP5B can also hydrolyze soluble inositol (1,4,5)-trisphosphate [I(1,4,5)P3] and inositol (1,3,4,5)-tetrakisphosphate [I(1,3,4,5)P4]. INPP5B participates in the endocytic pathway and in the early secretory pathway. In the latter, it may function in retrograde ERGIC (ER-to-Golgi intermediate compartment)-to-ER transport; it binds specific RAB proteins within the secretory pathway. In the endocytic pathway, it binds RAB5 and during endocytosis, may function in a RAB5-controlled cascade for converting PI(3,4,5)P3 to phosphatidylinositol 3-phosphate (PI3P). This cascade may link growth factor signaling and membrane dynamics. Mutation in OCRL1 is implicated in Lowe syndrome, an X-linked recessive multisystem disorder, which includes defects in eye, brain, and kidney function, and in Type 2 Dent's disease, a disorder with only the renal symptoms. OCRL-1 may have a role in membrane trafficking within the endocytic pathway and at the trans-Golgi network, and may participate in actin dynamics or signaling from endomembranes. OCRL1 and INPP5B have overlapping functions: deletion of both 5-phosphatases in mice is embryonic lethal, deletion of OCRL1 alone has no phenotype, and deletion of Inpp5b alone has only a mild phenotype (male sterility). Several of the proteins that interact with OCRL1 also bind INPP5B, for examples, inositol polyphosphate phosphatase interacting protein of 27kDa (IPIP27)A and B (also known as Ses1 and 2), and endocytic signaling adaptor APPL1. OCRL1, but not INPP5B, binds clathrin heavy chain, the plasma membrane AP2 adaptor subunit alpha-adaptin. In addition to this INPP5c domain, most proteins in this subfamily have a C-terminal RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  20 TWNVGTASPPPDVSSLLQLDSLGPtmDMYVIGLQEVN-SKITNFLSDLAFDDPWSIFFMTVLSPLG-YIKLSSVRMQGLL 97
Cdd:cd09093     7 TWNVNGQSPDESLRPWLSCDEEPP--DIYAIGFQELDlSAEAFLFNDSSREQEWVKAVERGLHPDAkYKKVKLIRLVGMM 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  98 LLIFVKHVHLPFIRDLHTQFTRTGLYGYWGNKGGVTIRMSLYGHTVCFMNCHLPAHMENTEQRLDDFEKILE-MQFE--G 174
Cdd:cd09093    85 LLVFVKKEHRQHIKEVAAETVGTGIMGKMGNKGGVAVRFQFHNTTFCFVNSHLAAHMEEVERRNQDYKDICArMKFEdpD 164

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*....
gi 1728920799 175 ENIPSALEHDVLFWFGDLNFRIADYGIHFVRESINNKRYNLLWEKDQLK 223
Cdd:cd09093   165 GPPLSISDHDVVFWLGDLNYRIQELPTEEVKELIEKNDLEELLKYDQLN 213

Catalytic inositol polyphosphate 5-phosphatase (INPP5c) domain of Saccharomyces cerevisiae Inp51p, Inp52p, and Inp53p, and related proteins; This subfamily contains the INPP5c domain of three Saccharomyces cerevisiae synaptojanin-like inositol polyphosphate 5-phosphatases (INP51, INP52, and INP53), Schizosaccharomyces pombe synaptojanin (SPsynaptojanin), and related proteins. It belongs to a family of Mg2+-dependent inositol polyphosphate 5-phosphatases, which hydrolyze the 5-phosphate from the inositol ring of various 5-position phosphorylated phosphoinositides (PIs) and inositol phosphates (IPs), and to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. In addition to this INPP5c domain, these proteins have an N-terminal catalytic Sac1-like domain (found in other proteins including the phophoinositide phosphatase Sac1p), and a C-terminal proline-rich domain (PRD). The Sac1 domain allows Inp52p and Inp53p to recognize and dephosphorylate a wider range of substrates including PI3P, PI4P, and PI(3,5)P2. The Sac1 domain of Inp51p is non-functional. Disruption of any two of INP51, INP52, and INP53, in S. cerevisiae leads to abnormal vacuolar and plasma membrane morphology. During hyperosmotic stress, Inp52p and Inp53p localize at actin patches, where they may facilitate the hydrolysis of PI(4,5)P2, and consequently promote actin rearrangement to regulate cell growth. SPsynaptojanin is also active against a range of soluble and lipid inositol phosphates, including I(1,4,5)P3, I(1,3,4,5)P4, I(1,4,5,6)P4, PI(4,5)P2, and PIP3. Transformation of S. cerevisiae with a plasmid expressing the SPsynaptojanin 5-phosphatase domain rescues inp51/inp52/inp53 triple-mutant strains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  14 LRLHLVTWNVGTASPPPDVSSLLQLDSLGPTMDMYVIGLQEV----NSKITNflSDLAFDDPWSIFFMTVL---SPLGYI 86
Cdd:cd09090     1 INIFVGTFNVNGKSYKDDLSSWLFPEENDELPDIVVIGLQEVveltAGQILN--SDPSKSSFWEKKIKTTLngrGGEKYV 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  87 KLSSVRMQGLLLLIFVKHVHLPFIRDLHTQFTRTGLYGYWGNKGGVTIRMSLYGHTVCFMNCHLPAHMENTEQRLDDFEK 166
Cdd:cd09090    79 LLRSEQLVGTALLFFVKESQLPKVKNVEGSTKKTGLGGMSGNKGAVAIRFDYGDTSFCFVTSHLAAGLTNYEERNNDYKT 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799 167 ILE-MQF-EGENIPSaleHDVLFWFGDLNFRIaDYGIHFVRESINNKRYNLLWEKDQLK---------PLVSEPLVTLNP 235
Cdd:cd09090   159 IARgLRFsRGRTIKD---HDHVIWLGDFNYRI-SLTNEDVRRFILNGKLDKLLEYDQLNqqmnagevfPGFSEGPITFPP 234

Catalytic inositol polyphosphate 5-phosphatase (INPP5c) domain of synaptojanins; This subfamily contains the INPP5c domains of two human synaptojanins, synaptojanin 1 (Synj1) and synaptojanin 2 (Synj2), and related proteins. It belongs to a family of Mg2+-dependent inositol polyphosphate 5-phosphatases, which hydrolyze the 5-phosphate from the inositol ring of various 5-position phosphorylated phosphoinositides (PIs) and inositol phosphates (IPs). They belong to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. Synj1 occurs as two main isoforms: a brain enriched 145 KDa protein (Synj1-145) and a ubiquitously expressed 170KDa protein (Synj1-170). Synj1-145 participates in clathrin-mediated endocytosis. The primary substrate of the Synj1-145 INPP5c domain is PI(4,5)P2, which it converts to PI4P. Synj1-145 may work with membrane curvature sensors/generators (such as endophilin) to remove PI(4,5)P2 from curved membranes. The recruitment of the INPP5c domain of Synj1-145 to endophilin-induced membranes leads to a fragmentation and condensation of these structures. The PI(4,5)P2 to PI4P conversion may cooperate with dynamin to produce membrane fission. In addition to this INPP5c domain, Synjs contain an N-terminal Sac1-like domain; the Sac1 domain can dephosphorylate a variety of phosphoinositides in vitro. Synj2 can hydrolyze phosphatidylinositol diphosphate (PIP2) to phosphatidylinositol phosphate (PIP). Synj2 occurs as multiple alternative splice variants in various tissues. These variants share the INPP5c domain and the Sac1 domain. Synj2A is recruited to the mitochondria via its interaction with OMP25 (a mitochondrial outer membrane protein). Synj2B is found at nerve terminals in the brain and at the spermatid manchette in testis. Synj2B undergoes further alternative splicing to give 2B1 and 2B2. In clathrin-mediated endocytosis, Synj2 participates in the formation of clathrin-coated pits, and perhaps also in vesicle decoating. Rac1 GTPase regulates the intracellular localization of Synj2 forms, but not Synj1. Synj2 may contribute to the role of Rac1 in cell migration and invasion, and is a potential target for therapeutic intervention in malignant tumors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  45 MDMYVIGLQEV----NSKITNFLSDLAFDdpWSIFFMTVLS-PLGYIKLSSVRMQGLLLLIFVKHVHLPFIRDLHTQFTR 119
Cdd:cd09089    51 VDIFAIGFEEMvdlnASNIVSASTTNQKE--WGEELQKTISrDHKYVLLTSEQLVGVCLFVFVRPQHAPFIRDVAVDTVK 128

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799 120 TGLYGYWGNKGGVTIRMSLYGHTVCFMNCHLPAHMENTEQRLDDFEKILE-MQFE-GENIPSaleHDVLFWFGDLNFRIa 197
Cdd:cd09089   129 TGLGGAAGNKGAVAIRFLLHSTSLCFVCSHFAAGQSQVKERNEDFAEIARkLSFPmGRTLDS---HDYVFWCGDFNYRI- 204

                         170       180
                  ....*....|....*....|....*
gi 1728920799 198 DYGIHFVRESINNKRYNLLWEKDQL 222
Cdd:cd09089   205 DLPNDEVKELVRNGDWLKLLEFDQL 229

Catalytic inositol polyphosphate 5-phosphatase (INPP5c) domain of SH2 domain containing inositol 5-phosphatase-2 and related proteins; This subfamily contains the INPP5c domain of SHIP2 (SH2 domain containing inositol 5-phosphatase-2, also called INPPL1) and related proteins. It belongs to a family of Mg2+-dependent inositol polyphosphate 5-phosphatases, which hydrolyze the 5-phosphate from the inositol ring of various 5-position phosphorylated phosphoinositides (PIs) and inositol phosphates (IPs), and to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. SHIP2 catalyzes the dephosphorylation of the PI, phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], to phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2]. SHIP2 is widely expressed, most prominently in brain, heart and in skeletal muscle. SHIP2 is an inhibitor of the insulin signaling pathway. It is implicated in actin structure remodeling, cell adhesion and cell spreading, receptor endocytosis and degradation, and in the JIP1-mediated JNK pathway. Its interacting partners include filamin/actin, p130Cas, Shc, Vinexin, Interesectin 1, and c-Jun NH2-terminal kinase (JNK)-interacting protein 1 (JIP1). A large variety of extracellular stimuli appear to lead to the tyrosine phosphorylation of SHIP2, including epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin, macrophage colony-stimulating factor (M-CSF) and hepatocyte growth factor (HGF). SHIP2 is localized to the cytosol in quiescent cells; following growth factor stimulation and /or cell adhesion, it relocalizes to membrane ruffles. In addition to this INPP5c domain, SHIP2 has an N-terminal SH2 domain, a C-terminal proline-rich domain (PRD), which includes a WW-domain binding motif (PPLP), an NPXY motif and a sterile alpha motif (SAM) domain. The gene encoding SHIP2 is a candidate for conferring a predisposition for type 2 diabetes; it has been suggested that suppression of SHIP2 may be of benefit in the treatment of obesity and thereby prevent type 2 diabetes. SHIP2 and SHIP1 have little overlap in their in vivo functions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  20 TWNVGTASPPPDVSSLLQLDSLGPTMD---------MYVIGLQEvNSkitnflsdlAFDDPWSIFFMTVLSPLGYIKLSS 90
Cdd:cd09101     7 TWNMGSVPPPKSLASWLTSRGLGKTLDettvtiphdIYVFGTQE-NS---------VGDREWVDFLRASLKELTDIDYQP 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  91 VRMQGLL---LLIFVKHVHLPFIRDLHTQFTRTGLYGYWGNKGGVTIRMSLYGHTVCFMNCHLPAHMENTEQRLDDFEKI 167
Cdd:cd09101    77 IALQCLWnikMVVLVKPEHENRISHVHTSSVKTGIANTLGNKGAVGVSFMFNGTSFGFVNCHLTSGNEKTHRRNQNYLDI 156

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1728920799 168 LEMQFEGENIPSALEHDV----LFWFGDLNFRIaDYGIHFVRESINNKRYNLLWEKDQL 222
Cdd:cd09101   157 LRSLSLGDKQLNAFDISLrfthLFWFGDLNYRL-DMDIQEILNYITRKEFDPLLAVDQL 214

Catalytic inositol polyphosphate 5-phosphatase (INPP5c) domain of Inositol polyphosphate-5-phosphatase E and related proteins; INPP5c domain of Inositol polyphosphate-5-phosphatase E (also called type IV or 72 kDa 5-phosphatase), rat pharbin, and related proteins. This subfamily belongs to a family of Mg2+-dependent inositol polyphosphate 5-phosphatases, which hydrolyze the 5-phosphate from the inositol ring of various 5-position phosphorylated phosphoinositides (PIs) and inositol phosphates (IPs), and to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. INPP5E hydrolyzes the 5-phosphate from PI(3,5)P2, PI(4,5)P2 and PI(3,4,5)P3, forming PI3P, PI4P, and PI(3,4)P2, respectively. It is a very potent PI(3,4,5)P3 5-phosphatase. Its intracellular localization is chiefly cytosolic, with pronounced perinuclear/Golgi localization. INPP5E also has an N-terminal proline rich domain (PRD) and a C-terminal CAAX motif. This protein is expressed in a variety of tissues, including the breast, brain, testis, and haemopoietic cells. It is differentially expressed in several cancers, for example, it is up-regulated in cervical cancer and down-regulated in stomach cancer. It is a candidate target for therapeutics of obesity and related disorders, as it is expressed in the hypothalamus, and following insulin stimulation, it undergoes tyrosine phosphorylation, associates with insulin receptor substrate-1, -2, and PI3-kinase, and become active as a 5-phosphatase. INPP5E may play a role, along with other 5-phosphatases SHIP2 and SKIP, in regulating glucose homoeostasis and energy metabolism. Mice deficient in INPPE5 develop a multi-organ disorder associated with structural defects of the primary cilium.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  12 RELRLHLVTWNV-GTASPPPDVSSLLQLDSLGPTMDMYVIGLQEVNSKitnflsdlafDDPWSIFFMTVLSPlGYIKLSS 90
Cdd:cd09095     3 RNVGIFVATWNMqGQKELPENLDDFLLPTSADFAQDIYVIGVQEGCSD----------RREWEIRLQETLGP-SHVLLHS 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  91 VRMQGLLLLIFVKhvhlpfiRDL---------HTQFTRTGlyGYWGNKGGVTIRMSLYGHTVCFMNCHLPAHMENTEQRL 161
Cdd:cd09095    72 ASHGVLHLAVFIR-------RDLiwfcsevesATVTTRIV--SQIKTKGALAISFTFFGTSFLFITSHFTSGDGKVKERV 142

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799 162 DDFEKI---LEMQFEGENIPSALEH-------DVLFWFGDLNFRIaDYGIHFVRESINNKR---YNLLWEKDQLKPLVSE 228
Cdd:cd09095   143 LDYNKIiqaLNLPRNVPTNPYKSESgdvttrfDEVFWFGDFNFRL-SGPRHLVDALINQGQevdVSALLQHDQLTREMSK 221

Catalytic inositol polyphosphate 5-phosphatase (INPP5c) domain of SH2 domain containing inositol polyphosphate 5-phosphatase-1 and -2, and related proteins; This subfamily contains the INPP5c domain of SHIP1 (SH2 domain containing inositol polyphosphate 5-phosphatase-1, also known as SHIP/INPP5D), and SHIP2 (also known as INPPL1). It belongs to a family of Mg2+-dependent inositol polyphosphate 5-phosphatases, which hydrolyze the 5-phosphate from the inositol ring of various 5-position phosphorylated phosphoinositides (PIs) and inositol phosphates (IPs), and to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. Both SHIP1 and -2 catalyze the dephosphorylation of the PI, phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], to phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2]. SHIP1 also converts inositol-1,3,4,5- polyphosphate [I(1,3,4,5)P4] to inositol-1,3,4-polyphosphate [I(1,3,4)P3]. SHIP1 and SHIP2 have little overlap in their in vivo functions. SHIP1 is a negative regulator of cell growth and plays a major part in mediating the inhibitory signaling in B cells; it is predominantly expressed in hematopoietic cells. SHIP2 is as an inhibitor of the insulin signaling pathway, and is implicated in actin structure remodeling, cell adhesion and cell spreading, receptor endocytosis and degradation, and in the JIP1-mediated JNK pathway. SHIP2 is widely expressed, most prominently in brain, heart and in skeletal muscle. In addition to this INPP5c domain, SHIP1 has an N-terminal SH2 domain, two NPXY motifs, and a C-terminal proline-rich region (PRD), while SHIP2 has an N-terminal SH2 domain, a C-terminal proline-rich domain (PRD), which includes a WW-domain binding motif (PPLP), an NPXY motif, and a sterile alpha motif (SAM) domain. The gene encoding SHIP2 is a candidate gene for conferring a predisposition for type 2 diabetes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  20 TWNVGTASPPPDVSSLLQLDSLGPTMD---------MYVIGLQEvnskitnflsDLAFDDPWSIFFMTVLSPLGYIKLSS 90
Cdd:cd09091     7 TWNMGSAPPPKNITSWFTSKGQGKTRDdvadyiphdIYVIGTQE----------DPLGEKEWLDLLRHSLKELTSLDYKP 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  91 VRMQGLL---LLIFVKHVHLPFIRDLHTQFTRTGLYGYWGNKGGVTIRMSLYGHTVCFMNCHLPAHMENTEQRLDDFEKI 167
Cdd:cd09091    77 IAMQTLWnirIVVLAKPEHENRISHVCTSSVKTGIANTLGNKGAVGVSFMFNGTSFGFVNSHLTSGSEKKLRRNQNYLNI 156

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1728920799 168 LEMQFEGE------NIPSALEHdvLFWFGDLNFRI--ADYGIHFVRESINNKRYNLLWEKDQLKPLVSEPLVTLNPEGE 238
Cdd:cd09091   157 LRFLSLGDkklsafNITHRFTH--LFWLGDLNYRLdlPIQEAENIIQKIEQQQFEPLLRHDQLNLEREEHKVFLRFSEE 233

Phosphodiesterase domain of human TDP2, a 5'-tyrosyl DNA phosphodiesterase, and related domains; Human TDP2, also known as TTRAP (TRAF/TNFR-associated factors, and tumor necrosis factor receptor/TNFR-associated protein), is a 5'-tyrosyl DNA phosphodiesterase. It is required for the efficient repair of topoisomerase II-induced DNA double strand breaks. The topoisomerase is covalently linked by a phosphotyrosyl bond to the 5'-terminus of the break. TDP2 cleaves the DNA 5'-phosphodiester bond and restores 5'-phosphate termini, needed for subsequent DNA ligation, and hence repair of the break. TDP2 and 3'-tyrosyl DNA phosphodiesterase (TDP1) are complementary activities; together, they allow cells to remove trapped topoisomerase from both 3'- and 5'-DNA termini. TTRAP has been reported as being involved in apoptosis, embryonic development, and transcriptional regulation, and it may inhibit the activation of nuclear factor-kB. This family belongs to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  16 LHLVTWNV-GTASPPPD-----VSSLLqldsLGPTMDmyVIGLQEVnskITNFLSDLAFDDPW-SIFFMTVLSPLgyikl 88
Cdd:cd09080     1 LKVLTWNVdFLDDVNLAermraILKLL----EELDPD--VIFLQEV---TPPFLAYLLSQPWVrKNYYFSEGPPS----- 66

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1728920799  89 SSVRMQGLLLLI--FVKHVHLPFirdLHTQFTRTGLYgywgnkggVTIRMSlYGHTVCFMNCHLPAHMENTEQRLDDFEK 166
Cdd:cd09080    67 PAVDPYGVLILSkkSLVVRRVPF---TSTRMGRNLLA--------AEINLG-SGEPLRLATTHLESLKSHSSERTAQLEE 134

                         170       180
                  ....*....|....*....|....*....
gi 1728920799 167 ILEMQFEgenipSALEHDVLFwFGDLNFR 195
Cdd:cd09080   135 IAKKLKK-----PPGAANVIL-GGDFNLR 157