O60346 (PHLP1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
PH domain leucine-rich repeat-containing 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
Short name=hSCOP

Gene names

Name:	PHLPP1
Synonyms:	KIAA0606, PHLPP, PLEKHE1, SCOP

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	1717 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Protein phosphatase that mediates dephosphorylation of 'Ser-473' of AKT1, 'Ser-660' of PRKCB isoform beta-II and 'Ser-657' of PRKCA. AKT1 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 AKT1 triggers apoptosis and suppression of tumor growth. Controls the phosphorylation of AKT2 and AKT3 more efficiently than that of AKT1. Dephosphorylation of PRKCA and PRKCB leads to their destabilization and degradation. Inhibits cancer cell proliferation and may act as a tumor suppressor. May act as a negative regulator of K-Ras signaling in membrane rafts. Ref.6 Ref.8 Ref.9 Ref.10
Catalytic activity	A phosphoprotein + H2O = a protein + phosphate. Ref.6
Cofactor	Binds 2 manganese ions per subunit By similarity. Ref.6
Enzyme regulation	Insensitive to okadaic acid. Ref.6
Subunit structure	Interacts with the nucleotide free form of K-Ras (KRAS) via its LRR repeats By similarity. Interacts with AKT2, AKT3 and PRKCB isoform beta-II. Ref.8 Ref.9
Subcellular location	Cytoplasm. Membrane; Peripheral membrane protein. Nucleus. Note: In colorectal cancer tissue, expression is concentrated at the lateral membrane of epithelial cells. Ref.8 Ref.10
Tissue specificity	In colorectal cancer tissue, expression is highest in the surface epithelium of normal colonic mucosa adjacent to the cancer tissue but is largely excluded from the crypt bases. Expression is lost or significantly decreased in 78% of tested tumors (at protein level). Ubiquitously expressed in non-cancerous tissues. Ref.6 Ref.10
Domain	The PH domain is required for interaction with PRKCB and its dephosphorylation.
Sequence similarities	Contains 21 LRR (leucine-rich) repeats. Contains 1 PH domain. Contains 1 PP2C-like domain.
Sequence caution	The sequence AAH14927.3 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence AAH82244.1 differs from that shown. Reason: Contaminating sequence. Potential poly-A sequence. The sequence AAI26278.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence BAA91980.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Ontologies

Keywords
Biological process	Apoptosis
Cellular component	Cytoplasm Membrane Nucleus
Coding sequence diversity	Polymorphism
Disease	Tumor suppressor
Domain	Leucine-rich repeat Repeat
Ligand	Manganese Metal-binding
Molecular function	Hydrolase Protein phosphatase
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW entrainment of circadian clock Inferred from electronic annotation. Source: Compara epidermal growth factor receptor signaling pathway Traceable author statement. Source: Reactome fibroblast growth factor receptor signaling pathway Traceable author statement. Source: Reactome innate immune response Traceable author statement. Source: Reactome metabolic process Inferred from electronic annotation. Source: GOC neurotrophin TRK receptor signaling pathway Traceable author statement. Source: Reactome phosphatidylinositol-mediated signaling Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW phospholipid binding Inferred from electronic annotation. Source: InterPro phosphoprotein phosphatase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1717	1717	PH domain leucine-rich repeat-containing protein phosphatase 1		PRO_0000057781
Regions
	Domain	536 – 636	101	PH
	Repeat	638 – 659	22	LRR 1
	Repeat	661 – 682	22	LRR 2
	Repeat	692 – 712	21	LRR 3
	Repeat	715 – 736	22	LRR 4
	Repeat	738 – 760	23	LRR 5
	Repeat	761 – 783	23	LRR 6
	Repeat	784 – 804	21	LRR 7
	Repeat	808 – 831	24	LRR 8
	Repeat	832 – 853	22	LRR 9
	Repeat	873 – 894	22	LRR 10
	Repeat	895 – 916	22	LRR 11
	Repeat	918 – 939	22	LRR 12
	Repeat	941 – 962	22	LRR 13
	Repeat	963 – 984	22	LRR 14
	Repeat	987 – 1008	22	LRR 15
	Repeat	1013 – 1033	21	LRR 16
	Repeat	1037 – 1058	22	LRR 17
	Repeat	1061 – 1082	22	LRR 18
	Repeat	1084 – 1105	22	LRR 19
	Repeat	1106 – 1127	22	LRR 20
	Repeat	1129 – 1150	22	LRR 21
	Domain	1165 – 1420	256	PP2C-like
	Motif	1715 – 1717	3	PDZ-binding
	Compositional bias	4 – 7	4	Poly-Ala
	Compositional bias	21 – 45	25	Poly-Ala
	Compositional bias	132 – 137	6	Poly-Ala
	Compositional bias	138 – 144	7	Poly-Ser
	Compositional bias	145 – 148	4	Poly-Ala
	Compositional bias	254 – 257	4	Poly-Ala
	Compositional bias	463 – 469	7	Poly-Pro
	Compositional bias	1682 – 1689	8	Poly-Gln
Sites
	Metal binding	1210	1	Manganese 1 By similarity
	Metal binding	1210	1	Manganese 2 By similarity
	Metal binding	1211	1	Manganese 1; via carbonyl oxygen By similarity
	Metal binding	1374	1	Manganese 2 By similarity
	Metal binding	1413	1	Manganese 2 By similarity
Natural variations
	Natural variant	1118	1	S → T. Corresponds to variant rs9950585 [ dbSNP | Ensembl ].		VAR_056725
Experimental info
	Mutagenesis	1715 – 1717	3	Missing: Loss of function in vivo, but does not abolishes intrinsic phosphatase activity. Ref.6
	Sequence conflict	691	1	T → A in BAA91980. Ref.5
	Sequence conflict	1062	1	L → F in AAH47653. Ref.4
	Sequence conflict	1083	1	R → S in BAA25532. Ref.2
	Sequence conflict	1227	1	D → V in BAA91980. Ref.5
	Sequence conflict	1490	1	V → M in AAH47653. Ref.4
	Sequence conflict	1580	1	Missing in AAH63519. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	O60346 [UniParc]. Last modified June 7, 2005. Version 3. Checksum: A4AB53F334EA8AB6	FASTA	1,717	184,672
	10 20 30 40 50 60 MEPAAAATVQ RLPELGREDR ASAPAAAAAA AAAAAAAAAA LAAAAGGGRS PEPALTPAAP 70 80 90 100 110 120 SGGNGSGSGA REEAPGEAPP GPLPGRAGGA GRRRRRGAPQ PIAGGAAPVP GAGGGANSLL 130 140 150 160 170 180 LRRGRLKRNL SAAAAAASSS SSSSAAAASH SPGAAGLPAS CSASASLCTR SLDRKTLLLK 190 200 210 220 230 240 HRQTLQLQPS DRDWVRHQLQ RGCVHVFDRH MASTYLRPVL CTLDTTAGEV AARLLQLGHK 250 260 270 280 290 300 GGGVVKVLGQ GPGAAAAREP AEPPPEAGPR LAPPEPRDSE VPPARSAPGA FGGPPRAPPA 310 320 330 340 350 360 DLPLPVGGPG GWSRRASPAP SDSSPGEPFV GGPVSSPRAP RPVVSDTESF SLSPSAESVS 370 380 390 400 410 420 DRLDPYSSGG GSSSSSEELE ADAASAPTGV PGQPRRPGHP AQPLPLPQTA SSPQPQQKAP 430 440 450 460 470 480 RAIDSPGGAV REGSCEEKAA AAVAPGGLQS TPGRSGVTAE KAPPPPPPPT LYVQLHGETT 490 500 510 520 530 540 RRLEAEEKPL QIQNDYLFQL GFGELWRVQE EGMDSEIGCL IRFYAGKPHS TGSSERIQLS 550 560 570 580 590 600 GMYNVRKGKM QLPVNRWTRR QVILCGTCLI VSSVKDSLTG KMHVLPLIGG KVEEVKKHQH 610 620 630 640 650 660 CLAFSSSGPQ SQTYYICFDT FTEYLRWLRQ VSKVASQRIS SVDLSCCSLE HLPANLFYSQ 670 680 690 700 710 720 DLTHLNLKQN FLRQNPSLPA ARGLNELQRF TKLKSLNLSN NHLGDFPLAV CSIPTLAELN 730 740 750 760 770 780 VSCNALRSVP AAVGVMHNLQ TFLLDGNFLQ SLPAELENMK QLSYLGLSFN EFTDIPEVLE 790 800 810 820 830 840 KLTAVDKLCM SGNCVETLRL QALRKMPHIK HVDLRLNVIR KLIADEVDFL QHVTQLDLRD 850 860 870 880 890 900 NKLGDLDAMI FNNIEVLHCE RNQLVTLDIC GYFLKALYAS SNELVQLDVY PVPNYLSYMD 910 920 930 940 950 960 VSRNRLENVP EWVCESRKLE VLDIGHNQIC ELPARLFCNS SLRKLLAGHN QLARLPERLE 970 980 990 1000 1010 1020 RTSVEVLDVQ HNQLLELPPN LLMKADSLRF LNASANKLES LPPATLSEET NSILQELYLT 1030 1040 1050 1060 1070 1080 NNSLTDKCVP LLTGHPHLKI LHMAYNRLQS FPASKMAKLE ELEEIDLSGN KLKAIPTTIM 1090 1100 1110 1120 1130 1140 NCRRMHTVIA HSNCIEVFPE VMQLPEIKCV DLSCNELSEV TLPENLPPKL QELDLTGNPR 1150 1160 1170 1180 1190 1200 LVLDHKTLEL LNNIRCFKID QPSTGDASGA PAVWSHGYTE ASGVKNKLCV AALSVNNFCD 1210 1220 1230 1240 1250 1260 NREALYGVFD GDRNVEVPYL LQCTMSDILA EELQKTKNEE EYMVNTFIVM QRKLGTAGQK 1270 1280 1290 1300 1310 1320 LGGAAVLCHI KHDPVDPGGS FTLTSANVGK CQTVLCRNGK PLPLSRSYIM SCEEELKRIK 1330 1340 1350 1360 1370 1380 QHKAIITEDG KVNGVTESTR ILGYTFLHPS VVPRPHVQSV LLTPQDEFFI LGSKGLWDSL 1390 1400 1410 1420 1430 1440 SVEEAVEAVR NVPDALAAAK KLCTLAQSYG CHDSISAVVV QLSVTEDSFC CCELSAGGAV 1450 1460 1470 1480 1490 1500 PPPSPGIFPP SVNMVIKDRP SDGLGVPSSS SGMASEISSE LSTSEMSSEV GSTASDEPPP 1510 1520 1530 1540 1550 1560 GALSENSPAY PSEQRCMLHP ICLSNSFQRQ LSSATFSSAF SDNGLDSDDE EPIEGVFTNG 1570 1580 1590 1600 1610 1620 SRVEVEVDIH CSRAKEKEKQ QHLLQVPAEA SDEGIVISAN EDEPGLPRKA DFSAVGTIGR 1630 1640 1650 1660 1670 1680 RRANGSVAPQ ERSHNVIEVA TDAPLRKPGG YFAAPAQPDP DDQFIIPPEL EEEVKEIMKH 1690 1700 1710 HQEQQQQQQP PPPPQLQPQL PRHYQLDQLP DYYDTPL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"DNA sequence and analysis of human chromosome 18." Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J. , Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L., Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K., Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R., Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S. Nature 437:551-555(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[2]	"Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro." Nagase T., Ishikawa K., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O. DNA Res. 5:31-39(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 349-1717. Tissue: Brain.
[3]	"Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones." Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T. DNA Res. 9:99-106(2002) [PubMed] [Europe PMC] [Abstract] Cited for: SEQUENCE REVISION.
[4]	"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] OF 475-1717. Tissue: Cerebellum, Hippocampus, Lymphoma, Melanoma and Retinoblastoma.
[5]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 495-1233. Tissue: Placenta.
[6]	"PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth." Gao T., Furnari F., Newton A.C. Mol. Cell 18:13-24(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, ENZYME ACTIVITY, COFACTOR, ENZYME REGULATION, TISSUE SPECIFICITY, MUTAGENESIS OF 1715-THR--LEU-1717.
[7]	"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: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[8]	"PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms." Brognard J., Sierecki E., Gao T., Newton A.C. Mol. Cell 25:917-931(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH AKT2 AND AKT3.
[9]	"The phosphatase PHLPP controls the cellular levels of protein kinase C." Gao T., Brognard J., Newton A.C. J. Biol. Chem. 283:6300-6311(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH PRKCB.
[10]	"Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis." Liu J., Weiss H.L., Rychahou P., Jackson L.N., Evers B.M., Gao T. Oncogene 28:994-1004(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases
EMBL GenBank DDBJ	AC015989 Genomic DNA. No translation available. AC022046 Genomic DNA. No translation available. AC027553 Genomic DNA. No translation available. AB011178 mRNA. Translation: BAA25532.2. BC010706 mRNA. Translation: AAH10706.1. BC014927 mRNA. Translation: AAH14927.3. Different initiation. BC047653 mRNA. Translation: AAH47653.1. BC063519 mRNA. Translation: AAH63519.1. BC082244 mRNA. Translation: AAH82244.1. Sequence problems. BC126277 mRNA. Translation: AAI26278.1. Different initiation. AK001924 mRNA. Translation: BAA91980.1. Different initiation.
IPI	IPI00297617.
PIR	T00258.
RefSeq	NP_919431.2. NM_194449.3.
UniGene	Hs.465337.
3D structure databases
ProteinModelPortal	O60346.
ModBase	Search...
Protein-protein interaction databases
IntAct	O60346. 16 interactions.
MINT	MINT-2796653.
STRING	9606.ENSP00000393405.
PTM databases
PhosphoSite	O60346.
Proteomic databases
PaxDb	O60346.
PeptideAtlas	O60346.
PRIDE	O60346.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000262719; ENSP00000262719; ENSG00000081913. ENST00000400316; ENSP00000383170; ENSG00000081913.
GeneID	23239.
KEGG	hsa:23239.
UCSC	uc021ule.1. human.
Organism-specific databases
CTD	23239.
GeneCards	GC18P060382.
H-InvDB	HIX0014494. HIX0174202.
HGNC	HGNC:20610. PHLPP1.
MIM	609396. gene.
neXtProt	NX_O60346.
PharmGKB	PA165429055.
HUGE	Search...
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG4886.
InParanoid	O60346.
KO	K16340.
OMA	CCELSAG.
OrthoDB	EOG4HMJ8G.
Enzyme and pathway databases
Reactome	REACT_111102. Signal Transduction. REACT_116125. Disease. REACT_6900. Immune System.
Gene expression databases
Bgee	O60346.
CleanEx	HS_PHLPP.
Genevestigator	O60346.
GermOnline	ENSG00000081913. Homo sapiens.
Family and domain databases
Gene3D	2.30.29.30. 1 hit. 3.60.40.10. 1 hit.
InterPro	IPR001611. Leu-rich_rpt. IPR011993. PH_like_dom. IPR001849. Pleckstrin_homology. IPR001932. PP2C-like. [Graphical view]
Pfam	PF00560. LRR_1. 2 hits. PF00481. PP2C. 1 hit. [Graphical view]
SMART	SM00233. PH. 1 hit. SM00332. PP2Cc. 1 hit. [Graphical view]
SUPFAM	SSF81606. PP2C-related. 1 hit.
PROSITE	PS51450. LRR. 17 hits. PS50003. PH_DOMAIN. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	PHLPP1. human.
GenomeRNAi	23239.
NextBio	44894.
SOURCE	Search...

Entry information

Entry name

PHLP1_HUMAN

Accession

Primary (citable) accession number: O60346
Secondary accession number(s): A1A4F5 , Q641Q7, Q6P4C4, Q6PJI6, Q86TN6, Q96FK2, Q9NUY1

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 7, 2005
Last sequence update:	June 7, 2005
Last modified:	May 29, 2013
This is version 124 of the entry and version 3 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.