PHLP1_RAT
ID PHLP1_RAT Reviewed; 1696 AA.
AC Q9WTR8;
DT 07-JUN-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 144.
DE RecName: Full=PH domain leucine-rich repeat protein phosphatase 1;
DE EC=3.1.3.16;
DE AltName: Full=Pleckstrin homology domain-containing family E member 1;
DE Short=PH domain-containing family E member 1;
DE AltName: Full=Suprachiasmatic nucleus circadian oscillatory protein;
GN Name=Phlpp1; Synonyms=Phlpp, Plekhe1, Scop;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RC TISSUE=Brain;
RX PubMed=10570941; DOI=10.1016/s0014-5793(99)01190-4;
RA Shimizu K., Okada M., Takano A., Nagai K.;
RT "SCOP, a novel gene product expressed in a circadian manner in rat
RT suprachiasmatic nucleus.";
RL FEBS Lett. 458:363-369(1999).
RN [2]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH KRAS.
RX PubMed=12594205; DOI=10.1074/jbc.m213214200;
RA Shimizu K., Okada M., Nagai K., Fukada Y.;
RT "Suprachiasmatic nucleus circadian oscillatory protein, a novel binding
RT partner of K-Ras in the membrane rafts, negatively regulates MAPK
RT pathway.";
RL J. Biol. Chem. 278:14920-14925(2003).
RN [3]
RP FUNCTION, ALTERNATIVE SPLICING, TISSUE SPECIFICITY (ISOFORMS 1 AND 2), AND
RP INDUCTION BY INSULIN.
RX PubMed=20089132; DOI=10.1111/j.1471-4159.2010.06609.x;
RA Kanan Y., Matsumoto H., Song H., Sokolov M., Anderson R.E., Rajala R.V.;
RT "Serine/threonine kinase akt activation regulates the activity of retinal
RT serine/threonine phosphatases, PHLPP and PHLPPL.";
RL J. Neurochem. 113:477-488(2010).
RN [4]
RP ALTERNATIVE SPLICING, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND
RP FUNCTION.
RX PubMed=20819118; DOI=10.1111/j.1471-4159.2010.06984.x;
RA Jackson T.C., Verrier J.D., Semple-Rowland S., Kumar A., Foster T.C.;
RT "PHLPP1 splice variants differentially regulate AKT and PKCalpha signaling
RT in hippocampal neurons: characterization of PHLPP proteins in the adult
RT hippocampus.";
RL J. Neurochem. 115:941-955(2010).
CC -!- FUNCTION: Protein phosphatase involved in regulation of Akt and PKC
CC signaling. Mediates dephosphorylation in the C-terminal domain
CC hydrophobic motif of members of the AGC Ser/Thr protein kinase family;
CC specifically acts on 'Ser-473' of AKT2 and AKT3, 'Ser-660' of PRKCB and
CC 'Ser-657' of PRKCA (PubMed:20819118). Isoform 2 seems to have a major
CC role in regulating Akt signaling in hippocampal neurons while isoform 1
CC may promote Akt and PKC activation and inhibit ERK signaling
CC (PubMed:20819118). Akt regulates the balance between cell survival and
CC apoptosis through a cascade that primarily alters the function of
CC transcription factors that regulate pro- and antiapoptotic genes.
CC Dephosphorylation of 'Ser-473' of Akt triggers apoptosis and
CC suppression of tumor growth. Dephosphorylation of PRKCA and PRKCB leads
CC to their destabilization and degradation. Dephosphorylates STK4 on
CC 'Thr-387' leading to STK4 activation and apoptosis (By similarity).
CC Dephosphorylates RPS6KB1 and is involved in regulation of cap-dependent
CC translation (By similarity). Inhibits cancer cell proliferation and may
CC act as a tumor suppressor (By similarity). Dephosphorylates RAF1
CC inhibiting its kinase activity (By similarity). May act as a negative
CC regulator of K-Ras signaling in membrane rafts (PubMed:12594205).
CC Involved in the hippocampus-dependent long-term memory formation (By
CC similarity). Involved in circadian control by regulating the
CC consolidation of circadian periodicity after resetting (By similarity).
CC Involved in development and function of regulatory T-cells (By
CC similarity). {ECO:0000250|UniProtKB:O60346,
CC ECO:0000250|UniProtKB:Q8CHE4, ECO:0000269|PubMed:12594205,
CC ECO:0000269|PubMed:20819118}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-seryl-[protein] = L-seryl-[protein] +
CC phosphate; Xref=Rhea:RHEA:20629, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:83421; EC=3.1.3.16;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-threonyl-[protein] = L-threonyl-[protein] +
CC phosphate; Xref=Rhea:RHEA:47004, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC COMP:11605, ChEBI:CHEBI:15377, ChEBI:CHEBI:30013, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:61977; EC=3.1.3.16;
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000250};
CC Note=Binds 2 manganese ions per subunit. {ECO:0000250};
CC -!- ACTIVITY REGULATION: Insensitive to okadaic acid. Deubiquitination by
CC WDR48-USP12 complex positively regulates PHLPP1 stability.
CC {ECO:0000250|UniProtKB:O60346}.
CC -!- SUBUNIT: Interacts with the nucleotide free form of K-Ras (KRAS) via
CC its LRR repeats (PubMed:12594205). Interacts with AKT2, AKT3 and PRKCB
CC isoform beta-II. Interacts with WDR48 and USP12 (By similarity).
CC {ECO:0000250|UniProtKB:O60346, ECO:0000269|PubMed:12594205}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12594205}. Membrane
CC {ECO:0000269|PubMed:12594205}; Peripheral membrane protein
CC {ECO:0000269|PubMed:12594205}.
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm
CC {ECO:0000269|PubMed:20819118}. Cell membrane
CC {ECO:0000269|PubMed:20819118}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus, nucleoplasm
CC {ECO:0000269|PubMed:20819118}. Nucleus membrane
CC {ECO:0000269|PubMed:20819118}. Cytoplasm {ECO:0000269|PubMed:20819118}.
CC Cell membrane {ECO:0000269|PubMed:20819118}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=beta;
CC IsoId=Q9WTR8-1; Sequence=Displayed;
CC Name=2; Synonyms=alpha;
CC IsoId=Q9WTR8-2; Sequence=VSP_057811;
CC -!- TISSUE SPECIFICITY: Mainly present in brain (at protein level)
CC (PubMed:10570941). Isoform 2 is more abundant in adult brain neurons
CC than isoform 1 in (PubMed:20819118). Isoforms 1 and 2 are expressed in
CC the retina but not found in rod outer segments (PubMed:20089132).
CC {ECO:0000269|PubMed:10570941, ECO:0000269|PubMed:20089132,
CC ECO:0000269|PubMed:20819118}.
CC -!- DEVELOPMENTAL STAGE: In the suprachiasmatic nucleus, it increases
CC during subjective night with a peak at midnight under constant dark
CC conditions. Expressed at a constant level in neurons throughout the
CC brain (at protein level) (PubMed:10570941). Isoform 2 expression
CC increases over development and maturation in the hippocampus. Isoform 1
CC expression is low in embryonic stages, increases during postnatal
CC development and is falling back to low embryonic levels in adulthood
CC (PubMed:20819118). {ECO:0000269|PubMed:10570941,
CC ECO:0000269|PubMed:20819118}.
CC -!- INDUCTION: Inhibited by insulin in a PI3K-dependent manner.
CC {ECO:0000269|PubMed:20089132}.
CC -!- DOMAIN: The PH domain is required for interaction with PRKCB and its
CC dephosphorylation. {ECO:0000250}.
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DR EMBL; AB023624; BAA77767.1; -; mRNA.
DR RefSeq; NP_067689.1; NM_021657.1. [Q9WTR8-1]
DR AlphaFoldDB; Q9WTR8; -.
DR SMR; Q9WTR8; -.
DR BioGRID; 248740; 1.
DR IntAct; Q9WTR8; 1.
DR STRING; 10116.ENSRNOP00000003840; -.
DR PaxDb; Q9WTR8; -.
DR PRIDE; Q9WTR8; -.
DR GeneID; 59265; -.
DR KEGG; rno:59265; -.
DR UCSC; RGD:621308; rat. [Q9WTR8-1]
DR CTD; 23239; -.
DR RGD; 621308; Phlpp1.
DR eggNOG; KOG0618; Eukaryota.
DR InParanoid; Q9WTR8; -.
DR OrthoDB; 172467at2759; -.
DR PhylomeDB; Q9WTR8; -.
DR Reactome; R-RNO-199418; Negative regulation of the PI3K/AKT network.
DR PRO; PR:Q9WTR8; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0017018; F:myosin phosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; IDA:RGD.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0007623; P:circadian rhythm; IEP:RGD.
DR GO; GO:0009649; P:entrainment of circadian clock; ISO:RGD.
DR GO; GO:0021766; P:hippocampus development; IEP:RGD.
DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IMP:UniProtKB.
DR GO; GO:0051898; P:negative regulation of protein kinase B signaling; IMP:UniProtKB.
DR GO; GO:0090038; P:negative regulation of protein kinase C signaling; IMP:UniProtKB.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; IMP:UniProtKB.
DR GO; GO:0090037; P:positive regulation of protein kinase C signaling; IMP:UniProtKB.
DR GO; GO:0006470; P:protein dephosphorylation; IDA:RGD.
DR GO; GO:0042981; P:regulation of apoptotic process; ISO:RGD.
DR GO; GO:0046328; P:regulation of JNK cascade; ISO:RGD.
DR GO; GO:0043408; P:regulation of MAPK cascade; ISO:RGD.
DR GO; GO:1900744; P:regulation of p38MAPK cascade; ISO:RGD.
DR GO; GO:0001932; P:regulation of protein phosphorylation; IMP:RGD.
DR GO; GO:0002667; P:regulation of T cell anergy; ISO:RGD.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR CDD; cd00143; PP2Cc; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR Gene3D; 3.60.40.10; -; 1.
DR Gene3D; 3.80.10.10; -; 3.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp.
DR InterPro; IPR032675; LRR_dom_sf.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR InterPro; IPR036457; PPM-type_dom_sf.
DR InterPro; IPR001932; PPM-type_phosphatase_dom.
DR InterPro; IPR001763; Rhodanese-like_dom.
DR Pfam; PF13516; LRR_6; 1.
DR Pfam; PF13855; LRR_8; 2.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF00481; PP2C; 1.
DR SMART; SM00369; LRR_TYP; 9.
DR SMART; SM00332; PP2Cc; 1.
DR SUPFAM; SSF81606; SSF81606; 1.
DR PROSITE; PS51450; LRR; 17.
DR PROSITE; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS51746; PPM_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Apoptosis; Cell membrane; Cytoplasm;
KW Hydrolase; Leucine-rich repeat; Manganese; Membrane; Metal-binding;
KW Nucleus; Phosphoprotein; Protein phosphatase; Reference proteome; Repeat;
KW Tumor suppressor.
FT CHAIN 1..1696
FT /note="PH domain leucine-rich repeat protein phosphatase 1"
FT /id="PRO_0000057783"
FT DOMAIN 499..599
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT REPEAT 601..622
FT /note="LRR 1"
FT REPEAT 624..645
FT /note="LRR 2"
FT REPEAT 655..676
FT /note="LRR 3"
FT REPEAT 678..699
FT /note="LRR 4"
FT REPEAT 701..722
FT /note="LRR 5"
FT REPEAT 724..746
FT /note="LRR 6"
FT REPEAT 836..857
FT /note="LRR 7"
FT REPEAT 858..879
FT /note="LRR 8"
FT REPEAT 881..902
FT /note="LRR 9"
FT REPEAT 904..925
FT /note="LRR 10"
FT REPEAT 926..947
FT /note="LRR 11"
FT REPEAT 950..971
FT /note="LRR 12"
FT REPEAT 976..996
FT /note="LRR 13"
FT REPEAT 1000..1021
FT /note="LRR 14"
FT REPEAT 1024..1045
FT /note="LRR 15"
FT REPEAT 1047..1068
FT /note="LRR 16"
FT REPEAT 1069..1090
FT /note="LRR 17"
FT REPEAT 1092..1113
FT /note="LRR 18"
FT DOMAIN 1138..1385
FT /note="PPM-type phosphatase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01082"
FT REGION 1..97
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 222..398
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1422..1473
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1610..1696
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 1694..1696
FT /note="PDZ-binding"
FT COMPBIAS 309..348
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 363..379
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1427..1473
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1631..1645
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 1173
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P35813"
FT BINDING 1173
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P35813"
FT BINDING 1174
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P35813"
FT BINDING 1337
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P35813"
FT BINDING 1376
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P35813"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:O60346"
FT MOD_RES 378
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O60346"
FT VAR_SEQ 1..475
FT /note="Missing (in isoform 2)"
FT /id="VSP_057811"
SQ SEQUENCE 1696 AA; 183364 MW; B4C3CC777B8BB6A9 CRC64;
MEPAAAAPAQ RLADPTGEDR APAAAAAAEG GRSPDSVLSA AAPSGGNGGA AREEAPCEAP
PGPLPGRAGG TGRRRRRGVP QPAAGGAAPV TAAGGGANSL LLRRGRLKRN LSAAASSSSS
PSSASSAAGG LPASCSASAS LCTRSLDRKT LLQKHRQLLQ LQPSDRDWVR HQLQRGCVHV
FDRHMASSYL RPVLCTLDTT AAEVAARLLQ LGHKGGGVVK VLGHGPPPAA APAASDQTPA
TELGRDVEPP PSSSTVGAVR GPARAPPADL PLPGGAWTRC APRVNPAPSD SSPGELFAGG
PCSPSRAPRP ASDTESFSLS PSAESVSDRL DPYSSGGGSS SSSEELEADP ATVLTGPSGP
PHHPVRSSQP RPPSPKTSAL LQPKAPTGVD GTGLVVGEGP GDDKAVAAAA PGVPLWTPGR
IRETVQKTSS PPSLYVQLHG ETTRRLEADE KPLQIQNDYL FQLGFGELWR VQEEGMDSEI
GCLIRFYAGK PHSTGSSERI QLSGMYNVRK GKMQLPVNRW TRRQVILCGT CLIVSSVKDS
SSGKMHVLPL IGGKVEEVKK HQHCLAFSSS GPQSQTYYIC FDTFTEYLRW LRQVSKVASQ
RISSVDLSCC SLEHLPANLF YSQDLTHLNL KQNFLRQNPS LPAARGLGEL QRFTKLKSLN
LSNNHLGAFP SAVCSIPTLA ELNVSCNALQ EVPAAVGAMQ NLQTFLLDGN FLQSLPAELE
NMHQLSYLGL SFNEFTDIPE VLEKLTAVDK LCMAGNCMET LRLQALRRMP HIKHVDLRLN
ILRKLITDEV DFLQHVTQLD LRDNKLGDLD AMIFNNIEVL HCERNQLVTL NICGYFLKAL
YASSNELVQL DVYPVPNYLS YMDVSRNCLE SVPEWVCESR KLEVLDIGHN QICELPARLF
CNSSLRKLLA GHNRLARLPE RLERTSVEVL DVQHNQIIEL PPNLLMKADS LRFLNASANK
LETLPPATLS EETSSILQEL YLTNNSLTDK CVPLLTGHPR LKILHMAYNR LQSFPASKMA
KLEELEEIDI SGNKLKAIPT TIMNCRRMHT VIAHSNCIEV FPEVMQLPEV KCVDLSCNEL
SEITLPENLP PKLQELDLTG NPRLALDHKS LELLNNIRCF KIDQPSAGDA SGAPAVWSHG
YTEASGVKNK LCVAALSVNN FRDNREALYG VFDGDRNVEV PYLLQCTMSD ILAEELQKTK
NEEEYMVNTF IVMQRKLGTA GQKLGGAAVL CHIRHDPVDL GGSFTLTSAN VGKCQTVLCR
NGKPLSLSRS YTMSCEEERK RIKQHKAIIT EDGKVNGVTE STRILGYTFL HPSVVPRPHV
QSVLLTPQDE FFILGSKGLW DSLSIEEAVE AVRNVPDALA AAKKLCTLAQ SYGCHDSISA
VVVQLSVTED SFCCCELSVG GSMPPPSPGI FPPSVSMVIK DRPSDGLGVP SSSSGMASEI
SSELSTSEMS SEVGSTASDE PPSGALSESS PAYPSEQRCM LHPVCLSNSF QRQLSSATFS
SAFSDNGLDS DDEEPIEGVF SNGSRVEVEV DIHCSRAKEK ERQQHLLQVP AEASDEGIVI
SANEDESGLS KKTDISAVGT IGRRRANGSV PPQERSHNVI EVATDAPLRK PGGYFAAPAQ
PDPDDQFIIP PELEEEVKEI MKHHQEQQQQ QQQQQQQQQQ QPPPPPQPPQ AQAQAQAQAQ
RPFQMDHLPD CYDTPL
