Reviewed, UniProtKB/Swiss-Prot Q12972 (PP1R8_HUMAN)

Names and origin

Protein names

Recommended name:
    Nuclear inhibitor of protein phosphatase 1
      Short name=NIPP-1
Alternative name(s):
    Protein phosphatase 1 regulatory inhibitor subunit 8
Including the following 1 domains:
    1- Recommended name:
            Activator of RNA decay
              EC=3.1.4.-
        Alternative name(s):
            ARD-1

Gene names

Name:	PPP1R8
Synonyms:	ARD1, NIPP1

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	351 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Inhibitor subunit of the major nuclear protein phosphatase-1 (PP-1). It has RNA-binding activity but does not cleave RNA and may target PP-1 to RNA-associated substrates. May also be involved in pre-mRNA splicing. Binds DNA and might act as a transcriptional repressor. Seems to be required for cell proliferation. Ref.8 Ref.10 Ref.11 Ref.13 Ref.15 Isoform Gamma is a site-specific single-strand endoribonuclease that cleaves single strand RNA 3' to purines and pyrimidines in A+U-rich regions. It generates 5'-phosphate termini at the site of cleavage. This isoform does not inhibit PP-1. May be implicated in mRNA splicing. Ref.8 Ref.10 Ref.11 Ref.13 Ref.15
Cofactor	Magnesium. Endoribonuclease function is magnesium-dependent.
Subunit structure	Interacts with phosphorylated CDC5L, SF3B1 and MELK. Interacts with EED, in a nucleic acid-stimulated manner. Part of a complex consisting of PPP1R8, EED, HDAC2 and PP-1. Part of the spliceosome. Ref.11 Ref.15 Ref.14 Ref.16
Subcellular location	Nucleus. Nucleus speckle. Note: Primarily, but not exclusively, nuclear. Ref.11 Ref.12 Isoform Gamma: Cytoplasm. Note: Found mainly in the cytoplasm. Ref.11 Ref.12
Tissue specificity	Ubiquitously expressed, with highest levels in heart and skeletal muscle, followed by brain, placenta, lung, liver and pancreas. Less abundant in kidney. The concentration and ratio between isoforms is cell-type dependent. Isoform Alpha (>90%) and isoform Beta were found in brain, heart and kidney. Isoform Gamma is mainly found in B-cells and T-lymphocytes, and has been found in 293 embryonic kidney cells. Ref.2 Ref.6
Domain	Has a basic N- and C-terminal and an acidic central domain.
Post-translational modification	May be inactivated by phosphorylation on Ser-199 or Ser-204 By similarity. Phosphorylated by Lyn in vitro on Tyr-264, and also on Tyr-335 in the presence of RNA.
Miscellaneous	A synthetic peptide, NIPP-1(330-351), is able to inhibit PP-1. Phosphorylation of Tyr-335 reduces PP-1 inhibition, whereas phosphorylation of Thr-346 or Ser-348 has no effect.
Sequence similarities	Contains 1 FHA domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation mRNA processing mRNA splicing
Cellular component	Cytoplasm Nucleus Spliceosome
Coding sequence diversity	Alternative splicing
Domain	Repeat
Ligand	DNA-binding Magnesium RNA-binding
Molecular function	Endonuclease Hydrolase Nuclease Protein phosphatase inhibitor Repressor
PTM	Phosphoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	RNA catabolic process Ref.7 Traceable author statement. Source: ProtInc RNA splicing Inferred from electronic annotation. Source: UniProtKB-KW mRNA processing Inferred from electronic annotation. Source: UniProtKB-KW regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-KW nuclear speck Inferred from electronic annotation. Source: UniProtKB-SubCell spliceosome Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	DNA binding Inferred from electronic annotation. Source: UniProtKB-KW RNA binding Ref.7 Traceable author statement. Source: ProtInc endonuclease activity Inferred from electronic annotation. Source: UniProtKB-KW magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from physical interaction. Source: IntAct protein serine/threonine phosphatase inhibitor activity Ref.6 Traceable author statement. Source: ProtInc ribonuclease E activity Ref.7 Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
NME2	P22392	1	EBI-716633,EBI-713693
PPP1CB	P62140	1	EBI-716633,EBI-352350

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform Alpha (identifier: Q12972-1)

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.

Isoform Beta (identifier: Q12972-2)

Also known as: Delta;

The sequence of this isoform differs from the canonical sequence as follows:
     1-142: Missing.

Isoform Gamma (identifier: Q12972-3)

Also known as: ARD-1;

The sequence of this isoform differs from the canonical sequence as follows:
     1-224: Missing.

Note: Found mainly in the cytoplasm. Ref.11 Ref.12

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 351	351	Nuclear inhibitor of protein phosphatase 1		PRO_0000071505
Regions
	Domain	49 – 101	53	FHA
	Region	1 – 142	142	Interaction with CDC5L, SF3B1 and MELK
	Region	143 – 224	82	Interaction with EED
	Region	191 – 200	10	Involved in PP-1 inhibition
	Region	200 – 203	4	Involved in PP-1 binding
	Region	310 – 329	20	Interaction with EED
	Region	330 – 351	22	RNA-binding
	Region	331 – 337	7	Involved in PP-1 inhibition
	Motif	185 – 209	25	Nuclear localization signal 1 Ref.12
	Motif	210 – 240	31	Nuclear localization signal 2 Ref.12
Amino acid modifications
	Modified residue	199	1	Phosphoserine By similarity
	Modified residue	204	1	Phosphoserine By similarity
	Modified residue	264	1	Phosphotyrosine; by LYN; in vitro Ref.10
	Modified residue	335	1	Phosphotyrosine Probable
Natural variations
	Alternative sequence	1 – 224	224	Missing in isoform Gamma.		VSP_005120
	Alternative sequence	1 – 142	142	Missing in isoform Beta.		VSP_005119
Experimental info
	Mutagenesis	68 – 71	4	SRVH → AAAA: Abolishes interaction with CDC5L, SF3B1 and MELK, and localization in nuclear speckles. No effect on repressor activity. Ref.11 Ref.14 Ref.16
	Mutagenesis	193 – 197	5	KRKRK → AAAAA: No effect on interaction with EED.
	Mutagenesis	195 – 197	3	KRK → AAA: Abolishes nuclear import; when associated with A-234--237-A.
	Mutagenesis	199	1	S → A or D: No change in subcellular location, no effect on interaction with EED or repressor activity; when associated with A-204 or D-204. Ref.15 Ref.12
	Mutagenesis	201	1	V → A: Reduces PP-1 binding, but no effect on subcellular location or repressor activity; when associated with A-203. Ref.15 Ref.12
	Mutagenesis	203	1	F → A: Reduces PP-1 binding, but no effect on subcellular location or repressor activity; when associated with A-201. Ref.15 Ref.12
	Mutagenesis	204	1	S → A or D: No change in subcellular location, no effect on interaction with EED or repressor activity; when associated with A-199 or D-199. Ref.15 Ref.12
	Mutagenesis	234 – 237	4	KKKR → AAAA: Abolishes nuclear import; when associated with A-195-197-A. Ref.12
	Mutagenesis	264	1	Y → D: Abolishes in vitro phosphorylation of isoform gamma by Lyn. Ref.10
	Mutagenesis	335	1	Y → D: Decreases the ability of isoform Gamma to bind and inhibit PP-1. Ref.10
	Mutagenesis	346	1	T → D: No effect on the ability of isoform Gamma to inhibit PP-1. Ref.10
	Mutagenesis	348	1	S → D: No effect on the ability of isoform Gamma to inhibit PP-1. Ref.10

Sequences

	Sequence		Length	Mass (Da)
	Isoform Alpha [UniParc]. Last modified December 1, 2000. Version 2. Checksum: 0A0E92B033E37641	FASTA	351	38,479
	10 20 30 40 50 60 MAAAANSGSS LPLFDCPTWA GKPPPGLHLD VVKGDKLIEK LIIDEKKYYL FGRNPDLCDF 70 80 90 100 110 120 TIDHQSCSRV HAALVYHKHL KRVFLIDLNS THGTFLGHIR LEPHKPQQIP IDSTVSFGAS 130 140 150 160 170 180 TRAYTLREKP QTLPSAVKGD EKMGGEDDEL KGLLGLPEEE TELDNLTEFN TAHNKRISTL 190 200 210 220 230 240 TIEEGNLDIQ RPKRKRKNSR VTFSEDDEII NPEDVDPSVG RFRNMVQTAV VPVKKKRVEG 250 260 270 280 290 300 PGSLGLEESG SRRMQNFAFS GGLYGGLPPT HSEAGSQPHG IHGTALIGGL PMPYPNLAPD 310 320 330 340 350 VDLTPVVPSA VNMNPAPNPA VYNPEAVNEP KKKKYAKEAW PGKKPTPSLL I
	Isoform Beta (Delta). Checksum: B8A896191A4AB026	FASTA	209	22,711
	10 20 30 40 50 60 MGGEDDELKG LLGLPEEETE LDNLTEFNTA HNKRISTLTI EEGNLDIQRP KRKRKNSRVT 70 80 90 100 110 120 FSEDDEIINP EDVDPSVGRF RNMVQTAVVP VKKKRVEGPG SLGLEESGSR RMQNFAFSGG 130 140 150 160 170 180 LYGGLPPTHS EAGSQPHGIH GTALIGGLPM PYPNLAPDVD LTPVVPSAVN MNPAPNPAVY 190 200 NPEAVNEPKK KKYAKEAWPG KKPTPSLLI
	Isoform Gamma (ARD-1). Checksum: D29E123EA36C9F94	FASTA	127	13,344
	10 20 30 40 50 60 MVQTAVVPVK KKRVEGPGSL GLEESGSRRM QNFAFSGGLY GGLPPTHSEA GSQPHGIHGT 70 80 90 100 110 120 ALIGGLPMPY PNLAPDVDLT PVVPSAVNMN PAPNPAVYNP EAVNEPKKKK YAKEAWPGKK PTPSLLI

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"ard-1: a human gene that reverses the effects of temperature-sensitive and deletion mutations in the Escherichia coli rne gene and encodes an activity producing RNase E-like cleavages." Wang M., Cohen S.N. Proc. Natl. Acad. Sci. U.S.A. 91:10591-10595(1994) [PubMed: 7524097] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM GAMMA). Tissue: B-cell.
[2]	"Organization and alternate splice products of the gene encoding nuclear inhibitor of protein phosphatase-1 (NIPP-1)." Van Eynde A., Perez-Callejon E., Schoenmakers E., Jacquemin M., Stalmans W., Bollen M. Eur. J. Biochem. 261:291-300(1999) [PubMed: 10103062] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS ALPHA AND BETA), ALTERNATIVE SPLICING, TISSUE SPECIFICITY. Tissue: Parathyroid and T-cell.
[3]	"Complete cDNA sequence of NIPP-1 from human breast cancer cells." Liu J.P., Yang Z., Li H. Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA). Tissue: Mammary cancer.
[4]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed: 16710414] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM BETA), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 34-351 (ISOFORM ALPHA). Tissue: Lymph.
[6]	"Molecular cloning of NIPP-1, a nuclear inhibitor of protein phosphatase-1, reveals homology with polypeptides involved in RNA processing." Van Eynde A., Wera S., Beullens M., Torrekens S., Van Leuven F., Stalmans W., Bollen M. J. Biol. Chem. 270:28068-28074(1995) [PubMed: 7499293] [Abstract] Cited for: TISSUE SPECIFICITY.
[7]	"ARD-1 cDNA from human cells encodes a site-specific single-strand endoribonuclease that functionally resembles Escherichia coli RNase E." Claverie-Martin F., Wang M., Cohen S.N. J. Biol. Chem. 272:13823-13828(1997) [PubMed: 9153239] [Abstract] Cited for: CHARACTERIZATION OF ISOFORM GAMMA.
[8]	"Mapping of the RNA-binding and endoribonuclease domains of NIPP1, a nuclear targeting subunit of protein phosphatase 1." Jin Q., Beullens M., Jagiello I., Van Eynde A., Vulsteke V., Stalmans W., Bollen M. Biochem. J. 342:13-19(1999) [PubMed: 10432294] [Abstract] Cited for: RNA-BINDING, CHARACTERIZATION OF ISOFORM GAMMA, FUNCTION.
[9]	"Alternative splicing regulates the production of ARD-1 endoribonuclease and NIPP-1, an inhibitor of protein phosphatase-1, as isoforms encoded by the same gene." Chang A.C.Y., Sohlberg B., Trinkle-Mulcahy L., Claverie-Martin F., Cohen P., Cohen S.N. Gene 240:45-55(1999) [PubMed: 10564811] [Abstract] Cited for: IDENTIFICATION OF ALTERNATIVE SPLICING IN ISOFORM GAMMA.
[10]	"The C-terminus of NIPP1 (nuclear inhibitor of protein phosphatase-1) contains a novel binding site for protein phosphatase-1 that is controlled by tyrosine phosphorylation and RNA binding." Beullens M., Vulsteke V., Van Eynde A., Jagiello I., Stalmans W., Bollen M. Biochem. J. 352:651-658(2000) [PubMed: 11104670] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF TYR-264; TYR-335; THR-346 AND SER-348, PHOSPHORYLATION AT TYR-264 AND TYR-335.
[11]	"NIPP1-mediated interaction of protein phosphatase-1 with CDC5L, a regulator of pre-mRNA splicing and mitotic entry." Boudrez A., Beullens M., Groenen P.M.A., Van Eynde A., Vulsteke V., Jagiello I., Murray M., Krainer A.R., Stalmans W., Bollen M. J. Biol. Chem. 275:25411-25417(2000) [PubMed: 10827081] [Abstract] Cited for: INTERACTION WITH CDC5L, SUBCELLULAR LOCATION, MUTAGENESIS OF 68-SER--HIS-71, FUNCTION.
[12]	"Nuclear and subnuclear targeting sequences of the protein phosphatase-1 regulator NIPP1." Jagiello I., Van Eynde A., Vulsteke V., Beullens M., Boudrez A., Keppens S., Stalmans W., Bollen M. J. Cell Sci. 113:3761-3768(2000) [PubMed: 11034904] [Abstract] Cited for: NUCLEAR LOCALIZATION SIGNALS, MUTAGENESIS OF 68-SER--HIS-71; 195-LYS--LYS-197; SER-199; VAL-201; PHE-203; SER-204 AND 234-LYS--ARG-237, SUBCELLULAR LOCATION.
[13]	"The protein phosphatase-1 regulator NIPP1 is also a splicing factor involved in a late step of spliceosome assembly." Beullens M., Bollen M. J. Biol. Chem. 277:19855-19860(2002) [PubMed: 11909864] [Abstract] Cited for: IDENTIFICATION AS PART OF THE SPLICEOSOME, FUNCTION.
[14]	"Phosphorylation-dependent interaction between the splicing factors SAP155 and NIPP1." Boudrez A., Beullens M., Waelkens E., Stalmans W., Bollen M. J. Biol. Chem. 277:31834-31841(2002) [PubMed: 12105215] [Abstract] Cited for: INTERACTION WITH SF3B1, MUTAGENESIS OF 68-SER--HIS-71.
[15]	"The protein phosphatase-1 (PP1) regulator, nuclear inhibitor of PP1 (NIPP1), interacts with the polycomb group protein, embryonic ectoderm development (EED), and functions as a transcriptional repressor." Jin Q., van Eynde A., Beullens M., Roy N., Thiel G., Stalmans W., Bollen M. J. Biol. Chem. 278:30677-30685(2003) [PubMed: 12788942] [Abstract] Cited for: DNA-BINDING, INTERACTION WITH EED, IDENTIFICATION IN A COMPLEX WITH EED; HDAC2 AND PP1, MUTAGENESIS OF 68-SER--HIS-71; 193-LYS--LYS-197; SER-199; VAL-201; PHE-203 AND SER-204, FUNCTION.
[16]	"Inhibition of spliceosome assembly by the cell cycle-regulated protein kinase MELK and involvement of splicing factor NIPP1." Vulsteke V., Beullens M., Boudrez A., Keppens S., Van Eynde A., Rider M.H., Stalmans W., Bollen M. J. Biol. Chem. 279:8642-8647(2004) [PubMed: 14699119] [Abstract] Cited for: INTERACTION WITH MELK, MUTAGENESIS OF 68-SER--HIS-71.
[17]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	U14575 mRNA. Translation: AAA64749.1. AF061958 mRNA. Translation: AAD31541.1. AF061959 mRNA. Translation: AAD31542.1. AF064757 , AF064751, AF064752, AF064753, AF064754, AF064755, AF064756 Genomic DNA. Translation: AAD24669.1. AF064757 , AF064754, AF064755, AF064756 Genomic DNA. Translation: AAD24670.1. AF126488 mRNA. Translation: AAD22486.1. AL020997, AL109927 Genomic DNA. Translation: CAI20577.1. AL109927, AL020997 Genomic DNA. Translation: CAI21780.1. BC001597 mRNA. Translation: AAH01597.1. BC013360 mRNA. Translation: AAH13360.1.
IPI	IPI00030383. IPI00142629. IPI00218794.
PIR	I38856.
RefSeq	NP_002704.1. NP_054829.2. NP_612568.1.
UniGene	Hs.533474
3D structure databases
ModBase	Search...
Protein-protein interaction databases
IntAct	Q12972. 8 interactions.
PTM databases
PhosphoSite	Q12972.
Proteomic databases
PeptideAtlas	Q12972.
PRIDE	Q12972.
Genome annotation databases
Ensembl	ENSG00000117751. Homo sapiens. [Contig view]
GeneID	5511.
KEGG	hsa:5511.
UCSC	uc001bov.1. human.
Organism-specific databases
GeneCards	GC01P028029.
H-InvDB	HIX0000304.
HGNC	HGNC:9296. PPP1R8.
MIM	602636. gene.
PharmGKB	PA33659.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	Q12972.
HOVERGEN	Q12972.
OMA	Q12972. VKKKRME.
Gene expression databases
ArrayExpress	Q12972.
Bgee	Q12972.
CleanEx	HS_PPP1R8.
Family and domain databases
InterPro	IPR000253. FHA. [Graphical view]
Gene3D	G3DSA:2.60.200.20. FHA. 1 hit.
Pfam	PF00498. FHA. 1 hit. [Graphical view]
SMART	SM00240. FHA. 1 hit. [Graphical view]
PROSITE	PS50006. FHA_DOMAIN. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	21316.
SOURCE	Search...

Entry information

Entry name

PP1R8_HUMAN

Accession

Primary (citable) accession number: Q12972
Secondary accession number(s): Q5TIF2 , Q6PKF6, Q9UBH1, Q9UBZ0

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 30, 2000
Last sequence update:	December 1, 2000
Last modified:	July 7, 2009
This is version 87 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)