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Protein

PH domain leucine-rich repeat protein phosphatase 1

Gene

Phlpp1

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Protein phosphatase involved in regulation of Akt and PKC signaling. Mediates dephosphorylation in the C-terminal domain hydrophobic motif of members of the AGC Ser/Thr protein kinase family; specifically acts on 'Ser-473' of AKT2 and AKT3, 'Ser-660' of PRKCB and 'Ser-657' of PRKCA (PubMed:20819118). Isoform 2 seems to have a major role in regulating Akt signaling in hippocampal neurons while isoform 1 may promote Akt and PKC activation and inhibit ERK signaling (PubMed:20819118). Akt regulates the balance between cell survival and apoptosis through a cascade that primarily alters the function of transcription factors that regulate pro- and antiapoptotic genes. Dephosphorylation of 'Ser-473' of Akt triggers apoptosis and suppression of tumor growth. Dephosphorylation of PRKCA and PRKCB leads to their destabilization and degradation. Dephosphorylates STK4 on 'Thr-387' leading to STK4 activation and apoptosis (By similarity). Dephosphorylates RPS6KB1 and is involved in regulation of cap-dependent translation (By similarity). Inhibits cancer cell proliferation and may act as a tumor suppressor (By similarity). Dephosphorylates RAF1 inhibiting its kinase activity (By similarity). May act as a negative regulator of K-Ras signaling in membrane rafts (PubMed:12594205). Involved in the hippocampus-dependent long-term memory formation (By similarity). Involved in circadian control by regulating the consolidation of circadian periodicity after resetting (By similarity). Involved in development and function of regulatory T cells (By similarity).By similarity2 Publications

Catalytic activityi

[a protein]-serine/threonine phosphate + H2O = [a protein]-serine/threonine + phosphate.

Cofactori

Mn2+By similarityNote: Binds 2 manganese ions per subunit.By similarity

Enzyme regulationi

Insensitive to okadaic acid (By similarity).By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi1173 – 11731Manganese 1By similarity
Metal bindingi1173 – 11731Manganese 2By similarity
Metal bindingi1174 – 11741Manganese 1; via carbonyl oxygenBy similarity
Metal bindingi1337 – 13371Manganese 2By similarity
Metal bindingi1376 – 13761Manganese 2By similarity

GO - Molecular functioni

  • metal ion binding Source: UniProtKB-KW
  • protein serine/threonine phosphatase activity Source: RGD

GO - Biological processi

  • apoptotic process Source: UniProtKB-KW
  • circadian rhythm Source: RGD
  • hippocampus development Source: RGD
  • negative regulation of protein kinase B signaling Source: RGD
  • negative regulation of protein kinase C signaling Source: RGD
  • protein dephosphorylation Source: RGD
  • regulation of protein phosphorylation Source: RGD
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protein phosphatase

Keywords - Biological processi

Apoptosis

Keywords - Ligandi

Manganese, Metal-binding

Names & Taxonomyi

Protein namesi
Recommended name:
PH domain leucine-rich repeat protein phosphatase 1 (EC:3.1.3.16)
Alternative name(s):
Pleckstrin homology domain-containing family E member 1
Short name:
PH domain-containing family E member 1
Suprachiasmatic nucleus circadian oscillatory protein
Gene namesi
Name:Phlpp1
Synonyms:Phlpp, Plekhe1, Scop
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
ProteomesiUP000002494 Componenti: Unplaced

Organism-specific databases

RGDi621308. Phlpp1.

Subcellular locationi

Isoform 1 :
Isoform 2 :

GO - Cellular componenti

  • cytoplasm Source: RGD
  • nuclear membrane Source: RGD
  • nucleoplasm Source: RGD
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Keywords - Diseasei

Tumor suppressor

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 16961696PH domain leucine-rich repeat protein phosphatase 1PRO_0000057783Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei1 – 11N-acetylmethionineBy similarity

Keywords - PTMi

Acetylation

Proteomic databases

PaxDbiQ9WTR8.
PRIDEiQ9WTR8.

Expressioni

Tissue specificityi

Mainly present in brain (at protein level) (PubMed:10570941). Isoform 2 is more abundant in adult brain neurons than isoform 1 in (PubMed:20819118). Isoforms 1 and 2 are expressed in the retina but not found in rod outer segments (PubMed:20089132).3 Publications

Developmental stagei

In the suprachiasmatic nucleus, it increases during subjective night with a peak at midnight under constant dark conditions. Expressed at a constant level in neurons throughout the brain (at protein level) (PubMed:10570941). Isoform 2 expression increases over development and maturation in the hippocampus. Isoform 1 expression is low in embryonic stages, increases during postnatal development and is falling back to low embryonic levels in adulthood (PubMed:20819118).2 Publications

Inductioni

Inhibited by insulin in a PI3K-dependent manner.1 Publication

Gene expression databases

GenevisibleiQ9WTR8. RN.

Interactioni

Subunit structurei

Interacts with the nucleotide free form of K-Ras (KRAS) via its LRR repeats. Interacts with AKT2, AKT3 and PRKCB isoform beta-II (By similarity).By similarity

Protein-protein interaction databases

BioGridi248740. 1 interaction.
IntActiQ9WTR8. 2 interactions.
STRINGi10116.ENSRNOP00000003840.

Structurei

3D structure databases

ProteinModelPortaliQ9WTR8.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini499 – 599101PHPROSITE-ProRule annotationAdd
BLAST
Repeati601 – 62222LRR 1Add
BLAST
Repeati624 – 64522LRR 2Add
BLAST
Repeati655 – 67622LRR 3Add
BLAST
Repeati678 – 69922LRR 4Add
BLAST
Repeati701 – 72222LRR 5Add
BLAST
Repeati724 – 74623LRR 6Add
BLAST
Repeati836 – 85722LRR 7Add
BLAST
Repeati858 – 87922LRR 8Add
BLAST
Repeati881 – 90222LRR 9Add
BLAST
Repeati904 – 92522LRR 10Add
BLAST
Repeati926 – 94722LRR 11Add
BLAST
Repeati950 – 97122LRR 12Add
BLAST
Repeati976 – 99621LRR 13Add
BLAST
Repeati1000 – 102122LRR 14Add
BLAST
Repeati1024 – 104522LRR 15Add
BLAST
Repeati1047 – 106822LRR 16Add
BLAST
Repeati1069 – 109022LRR 17Add
BLAST
Repeati1092 – 111322LRR 18Add
BLAST
Domaini1138 – 1385248PPM-type phosphatasePROSITE-ProRule annotationAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi1694 – 16963PDZ-binding

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi4 – 96Poly-Ala
Compositional biasi21 – 288Poly-Ala
Compositional biasi116 – 12611Poly-SerAdd
BLAST
Compositional biasi339 – 3435Poly-Ser
Compositional biasi405 – 4106Poly-Ala
Compositional biasi1431 – 14344Poly-Ser
Compositional biasi1645 – 166117Poly-GlnAdd
BLAST
Compositional biasi1662 – 16698Poly-Pro

Domaini

The PH domain is required for interaction with PRKCB and its dephosphorylation.By similarity

Sequence similaritiesi

Contains 18 LRR (leucine-rich) repeats.Curated
Contains 1 PH domain.PROSITE-ProRule annotation
Contains 1 PPM-type phosphatase domain.PROSITE-ProRule annotation

Keywords - Domaini

Leucine-rich repeat, Repeat

Phylogenomic databases

eggNOGiCOG4886.
HOGENOMiHOG000115529.
InParanoidiQ9WTR8.
KOiK16340.
PhylomeDBiQ9WTR8.

Family and domain databases

Gene3Di2.30.29.30. 1 hit.
3.60.40.10. 1 hit.
InterProiIPR001611. Leu-rich_rpt.
IPR011993. PH-like_dom.
IPR001849. PH_domain.
IPR001932. PPM-type_phosphatase_dom.
[Graphical view]
PfamiPF00560. LRR_1. 2 hits.
PF13855. LRR_8. 2 hits.
PF00481. PP2C. 1 hit.
[Graphical view]
SMARTiSM00233. PH. 1 hit.
SM00332. PP2Cc. 1 hit.
[Graphical view]
SUPFAMiSSF81606. SSF81606. 1 hit.
PROSITEiPS51450. LRR. 17 hits.
PS50003. PH_DOMAIN. 1 hit.
PS51746. PPM_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9WTR8-1) [UniParc]FASTAAdd to basket

Also known as: beta

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.

« Hide

        10         20         30         40         50
MEPAAAAPAQ RLADPTGEDR APAAAAAAEG GRSPDSVLSA AAPSGGNGGA
60 70 80 90 100
AREEAPCEAP PGPLPGRAGG TGRRRRRGVP QPAAGGAAPV TAAGGGANSL
110 120 130 140 150
LLRRGRLKRN LSAAASSSSS PSSASSAAGG LPASCSASAS LCTRSLDRKT
160 170 180 190 200
LLQKHRQLLQ LQPSDRDWVR HQLQRGCVHV FDRHMASSYL RPVLCTLDTT
210 220 230 240 250
AAEVAARLLQ LGHKGGGVVK VLGHGPPPAA APAASDQTPA TELGRDVEPP
260 270 280 290 300
PSSSTVGAVR GPARAPPADL PLPGGAWTRC APRVNPAPSD SSPGELFAGG
310 320 330 340 350
PCSPSRAPRP ASDTESFSLS PSAESVSDRL DPYSSGGGSS SSSEELEADP
360 370 380 390 400
ATVLTGPSGP PHHPVRSSQP RPPSPKTSAL LQPKAPTGVD GTGLVVGEGP
410 420 430 440 450
GDDKAVAAAA PGVPLWTPGR IRETVQKTSS PPSLYVQLHG ETTRRLEADE
460 470 480 490 500
KPLQIQNDYL FQLGFGELWR VQEEGMDSEI GCLIRFYAGK PHSTGSSERI
510 520 530 540 550
QLSGMYNVRK GKMQLPVNRW TRRQVILCGT CLIVSSVKDS SSGKMHVLPL
560 570 580 590 600
IGGKVEEVKK HQHCLAFSSS GPQSQTYYIC FDTFTEYLRW LRQVSKVASQ
610 620 630 640 650
RISSVDLSCC SLEHLPANLF YSQDLTHLNL KQNFLRQNPS LPAARGLGEL
660 670 680 690 700
QRFTKLKSLN LSNNHLGAFP SAVCSIPTLA ELNVSCNALQ EVPAAVGAMQ
710 720 730 740 750
NLQTFLLDGN FLQSLPAELE NMHQLSYLGL SFNEFTDIPE VLEKLTAVDK
760 770 780 790 800
LCMAGNCMET LRLQALRRMP HIKHVDLRLN ILRKLITDEV DFLQHVTQLD
810 820 830 840 850
LRDNKLGDLD AMIFNNIEVL HCERNQLVTL NICGYFLKAL YASSNELVQL
860 870 880 890 900
DVYPVPNYLS YMDVSRNCLE SVPEWVCESR KLEVLDIGHN QICELPARLF
910 920 930 940 950
CNSSLRKLLA GHNRLARLPE RLERTSVEVL DVQHNQIIEL PPNLLMKADS
960 970 980 990 1000
LRFLNASANK LETLPPATLS EETSSILQEL YLTNNSLTDK CVPLLTGHPR
1010 1020 1030 1040 1050
LKILHMAYNR LQSFPASKMA KLEELEEIDI SGNKLKAIPT TIMNCRRMHT
1060 1070 1080 1090 1100
VIAHSNCIEV FPEVMQLPEV KCVDLSCNEL SEITLPENLP PKLQELDLTG
1110 1120 1130 1140 1150
NPRLALDHKS LELLNNIRCF KIDQPSAGDA SGAPAVWSHG YTEASGVKNK
1160 1170 1180 1190 1200
LCVAALSVNN FRDNREALYG VFDGDRNVEV PYLLQCTMSD ILAEELQKTK
1210 1220 1230 1240 1250
NEEEYMVNTF IVMQRKLGTA GQKLGGAAVL CHIRHDPVDL GGSFTLTSAN
1260 1270 1280 1290 1300
VGKCQTVLCR NGKPLSLSRS YTMSCEEERK RIKQHKAIIT EDGKVNGVTE
1310 1320 1330 1340 1350
STRILGYTFL HPSVVPRPHV QSVLLTPQDE FFILGSKGLW DSLSIEEAVE
1360 1370 1380 1390 1400
AVRNVPDALA AAKKLCTLAQ SYGCHDSISA VVVQLSVTED SFCCCELSVG
1410 1420 1430 1440 1450
GSMPPPSPGI FPPSVSMVIK DRPSDGLGVP SSSSGMASEI SSELSTSEMS
1460 1470 1480 1490 1500
SEVGSTASDE PPSGALSESS PAYPSEQRCM LHPVCLSNSF QRQLSSATFS
1510 1520 1530 1540 1550
SAFSDNGLDS DDEEPIEGVF SNGSRVEVEV DIHCSRAKEK ERQQHLLQVP
1560 1570 1580 1590 1600
AEASDEGIVI SANEDESGLS KKTDISAVGT IGRRRANGSV PPQERSHNVI
1610 1620 1630 1640 1650
EVATDAPLRK PGGYFAAPAQ PDPDDQFIIP PELEEEVKEI MKHHQEQQQQ
1660 1670 1680 1690
QQQQQQQQQQ QPPPPPQPPQ AQAQAQAQAQ RPFQMDHLPD CYDTPL
Length:1,696
Mass (Da):183,364
Last modified:November 1, 1999 - v1
Checksum:iB4C3CC777B8BB6A9
GO
Isoform 2 (identifier: Q9WTR8-2) [UniParc]FASTAAdd to basket

Also known as: alpha

The sequence of this isoform differs from the canonical sequence as follows:
     1-475: Missing.

Show »
Length:1,221
Mass (Da):135,176
Checksum:i4BD62377AFDF839F
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 475475Missing in isoform 2. VSP_057811Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB023624 mRNA. Translation: BAA77767.1.
RefSeqiNP_067689.1. NM_021657.1.
UniGeneiRn.163214.

Genome annotation databases

GeneIDi59265.
KEGGirno:59265.
UCSCiRGD:621308. rat.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB023624 mRNA. Translation: BAA77767.1.
RefSeqiNP_067689.1. NM_021657.1.
UniGeneiRn.163214.

3D structure databases

ProteinModelPortaliQ9WTR8.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi248740. 1 interaction.
IntActiQ9WTR8. 2 interactions.
STRINGi10116.ENSRNOP00000003840.

Proteomic databases

PaxDbiQ9WTR8.
PRIDEiQ9WTR8.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi59265.
KEGGirno:59265.
UCSCiRGD:621308. rat.

Organism-specific databases

CTDi23239.
RGDi621308. Phlpp1.

Phylogenomic databases

eggNOGiCOG4886.
HOGENOMiHOG000115529.
InParanoidiQ9WTR8.
KOiK16340.
PhylomeDBiQ9WTR8.

Miscellaneous databases

NextBioi611783.
PROiQ9WTR8.

Gene expression databases

GenevisibleiQ9WTR8. RN.

Family and domain databases

Gene3Di2.30.29.30. 1 hit.
3.60.40.10. 1 hit.
InterProiIPR001611. Leu-rich_rpt.
IPR011993. PH-like_dom.
IPR001849. PH_domain.
IPR001932. PPM-type_phosphatase_dom.
[Graphical view]
PfamiPF00560. LRR_1. 2 hits.
PF13855. LRR_8. 2 hits.
PF00481. PP2C. 1 hit.
[Graphical view]
SMARTiSM00233. PH. 1 hit.
SM00332. PP2Cc. 1 hit.
[Graphical view]
SUPFAMiSSF81606. SSF81606. 1 hit.
PROSITEiPS51450. LRR. 17 hits.
PS50003. PH_DOMAIN. 1 hit.
PS51746. PPM_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "SCOP, a novel gene product expressed in a circadian manner in rat suprachiasmatic nucleus."
    Shimizu K., Okada M., Takano A., Nagai K.
    FEBS Lett. 458:363-369(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
    Tissue: Brain.
  2. "Suprachiasmatic nucleus circadian oscillatory protein, a novel binding partner of K-Ras in the membrane rafts, negatively regulates MAPK pathway."
    Shimizu K., Okada M., Nagai K., Fukada Y.
    J. Biol. Chem. 278:14920-14925(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH KRAS.
  3. "Serine/threonine kinase akt activation regulates the activity of retinal serine/threonine phosphatases, PHLPP and PHLPPL."
    Kanan Y., Matsumoto H., Song H., Sokolov M., Anderson R.E., Rajala R.V.
    J. Neurochem. 113:477-488(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, ALTERNATIVE SPLICING, TISSUE SPECIFICITY (ISOFORMS 1 AND 2), INDUCTION BY INSULIN.
  4. "PHLPP1 splice variants differentially regulate AKT and PKCalpha signaling in hippocampal neurons: characterization of PHLPP proteins in the adult hippocampus."
    Jackson T.C., Verrier J.D., Semple-Rowland S., Kumar A., Foster T.C.
    J. Neurochem. 115:941-955(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: ALTERNATIVE SPLICING, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, FUNCTION.

Entry informationi

Entry nameiPHLP1_RAT
AccessioniPrimary (citable) accession number: Q9WTR8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 7, 2005
Last sequence update: November 1, 1999
Last modified: July 22, 2015
This is version 108 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.