Q15599 (NHRF2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Na(+)/H(+) exchange regulatory cofactor NHE-RF2
Short name=NHERF-2

Alternative name(s):
NHE3 kinase A regulatory protein E3KARP
SRY-interacting protein 1
Short name=SIP-1
Sodium-hydrogen exchanger regulatory factor 2
Solute carrier family 9 isoform A3 regulatory factor 2
Tyrosine kinase activator protein 1
Short name=TKA-1

Gene names

Name:	SLC9A3R2
Synonyms:	NHERF2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	337 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May also act as scaffold protein in the nucleus. Ref.3 Ref.9
Subunit structure	Homodimer, and heterodimer with SLC9A3R1. Binds PDZK1. Found in a complex with EZR, PODXL and SLC9A3R2 By similarity. Interacts (via the PDZ domains) with PODXL (via the C-terminal PDZ-binding motif DTHL); interaction is detected in glomerular epithelium cells By similarity. Binds ADRB2, SLC9A3, P2RY1, P2YR2, SRY, RDX and LPAR2. Interacts with MCC and PODXL. Interacts with SGK1 and KCNJ1/ROMK1. Ref.1 Ref.3 Ref.5 Ref.9 Ref.10 Ref.11 Ref.13 Ref.15
Subcellular location	Endomembrane system; Peripheral membrane protein. Nucleus. Apical cell membrane By similarity. Note: Localizes with EZR and PODXL at the apical cell membrane of glomerular epithelium cells and the sides of the food processes By similarity. Nuclear, in a punctate pattern. Ref.1
Tissue specificity	Widely expressed. Ref.1 Ref.3
Sequence similarities	Contains 2 PDZ (DHR) domains.
Sequence caution	The sequence AAH14513.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened. The sequence CAA90511.1 differs from that shown. Reason: Frameshift at position 309.

Ontologies

Keywords
Cellular component	Cell membrane Membrane Nucleus
Coding sequence diversity	Alternative splicing
Domain	Repeat
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	protein complex assembly Traceable author statement. Source: ProtInc
Cellular component	apical plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell endomembrane system Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Traceable author statement. Source: ProtInc
Molecular function	beta-catenin binding Inferred from physical interaction. Source: UniProtKB phosphatase binding Inferred from physical interaction. Source: UniProtKB protein C-terminus binding Inferred from physical interaction. Source: UniProtKB receptor binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CFTR	P13569	4	EBI-1149760,EBI-349854
LPAR2	Q9HBW0	2	EBI-1149760,EBI-765995

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q15599-1)

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 2 (identifier: Q15599-2)

The sequence of this isoform differs from the canonical sequence as follows:
     285-295: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 337

337

Na(+)/H(+) exchange regulatory cofactor NHE-RF2

PRO_0000096805

Regions

Domain

11 – 90

80

PDZ 1

Domain

150 – 230

81

PDZ 2

Amino acid modifications

Modified residue

183

1

Phosphoserine Ref.14

Modified residue

254

1

Phosphoserine Ref.14

Modified residue

272

1

Phosphoserine By similarity

Modified residue

275

1

Phosphoserine Ref.12

Natural variations

Alternative sequence

285 – 295

11

Missing in isoform 2.

VSP_009378

Experimental info

Sequence conflict

51

1

Missing in CAA90511. Ref.2

Secondary structure

1

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337

Helix Strand Turn

Details...

Beta strand

10 – 15

6

Beta strand

23 – 27

5

Beta strand

34 – 39

6

Helix

44 – 47

4

Beta strand

54 – 59

6

Helix

69 – 77

9

Beta strand

82 – 89

8

Beta strand

150 – 155

6

Beta strand

163 – 167

5

Beta strand

169 – 179

11

Helix

184 – 188

5

Beta strand

195 – 199

5

Helix

209 – 216

8

Beta strand

219 – 228

10

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 16, 2004. Version 2. Checksum: 4F5D341590D22ED7	FASTA	337	37,414
	10 20 30 40 50 60 MAAPEPLRPR LCRLVRGEQG YGFHLHGEKG RRGQFIRRVE PGSPAEAAAL RAGDRLVEVN 70 80 90 100 110 120 GVNVEGETHH QVVQRIKAVE GQTRLLVVDQ ETDEELRRRQ LTCTEEMAQR GLPPAHDPWE 130 140 150 160 170 180 PKPDWAHTGS HSSEAGKKDV SGPLRELRPR LCHLRKGPQG YGFNLHSDKS RPGQYIRSVD 190 200 210 220 230 240 PGSPAARSGL RAQDRLIEVN GQNVEGLRHA EVVASIKARE DEARLLVVDP ETDEHFKRLR 250 260 270 280 290 300 VTPTEEHVEG PLPSPVTNGT SPAQLNGGSA CSSRSDLPGS DKDTEDGSAW KQDPFQESGL 310 320 330 HLSPTAAEAK EKARAMRVNK RAPQMDWNRK REIFSNF
	Isoform 2 [UniParc]. Checksum: 59FB231865D896DC	FASTA	326	36,152
	10 20 30 40 50 60 MAAPEPLRPR LCRLVRGEQG YGFHLHGEKG RRGQFIRRVE PGSPAEAAAL RAGDRLVEVN 70 80 90 100 110 120 GVNVEGETHH QVVQRIKAVE GQTRLLVVDQ ETDEELRRRQ LTCTEEMAQR GLPPAHDPWE 130 140 150 160 170 180 PKPDWAHTGS HSSEAGKKDV SGPLRELRPR LCHLRKGPQG YGFNLHSDKS RPGQYIRSVD 190 200 210 220 230 240 PGSPAARSGL RAQDRLIEVN GQNVEGLRHA EVVASIKARE DEARLLVVDP ETDEHFKRLR 250 260 270 280 290 300 VTPTEEHVEG PLPSPVTNGT SPAQLNGGSA CSSRSDLPGS DKDTQESGLH LSPTAAEAKE 310 320 KARAMRVNKR APQMDWNRKR EIFSNF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The human testis determining factor SRY binds a nuclear factor containing PDZ protein interaction domains." Poulat F., de Santa Barbara P., Desclozeaux M., Soullier S., Moniot B., Bonneaud N., Boizet B., Berta P. J. Biol. Chem. 272:7167-7172(1997) [PubMed: 9054412] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), INTERACTION WITH SRY, TISSUE SPECIFICITY, SUBCELLULAR LOCATION. Tissue: Cervix carcinoma, Fetal brain and Testis.
[2]	"Identification of EBP50: a PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family." Reczek D., Berryman M., Bretscher A. J. Cell Biol. 139:169-179(1997) [PubMed: 9314537] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Placenta.
[3]	"cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein." Yun C.H.C., Oh S., Zizak M., Steplock D., Tsao S., Tse C.-M., Weinman E.J., Donowitz M. Proc. Natl. Acad. Sci. U.S.A. 94:3010-3015(1997) [PubMed: 9096337] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH SLC9A3, TISSUE SPECIFICITY. Tissue: Embryo.
[4]	"Genomic structure and sequence of a human homologue (NTHL1/NTH1) of Escherichia coli endonuclease III with those of the adjacent parts of TSC2 and SLC9A3R2 genes." Imai K., Sarker A.H., Akiyama K., Ikeda S., Yao M., Tsutsui K., Shohmori T., Seki S. Gene 222:287-295(1998) [PubMed: 9831664] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins." Hall R.A., Ostedgaard L.S., Premont R.T., Blitzer J.T., Rahman N., Welsh M.J., Lefkowitz R.J. Proc. Natl. Acad. Sci. U.S.A. 95:8496-8501(1998) [PubMed: 9671706] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH ADRB2; P2RY1 AND P2YR2. Tissue: Lung.
[6]	"The sequence and analysis of duplication-rich human chromosome 16." Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J. , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A. Nature 432:988-994(2004) [PubMed: 15616553] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	"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 1). Tissue: Kidney and Testis.
[9]	"cAMP-induced phosphorylation and inhibition of Na(+)/H(+) exchanger 3 (NHE3) are dependent on the presence but not the phosphorylation of NHE regulatory factor." Zizak M., Lamprecht G., Steplock D., Tariq N., Shenolikar S., Donowitz M., Yun C.H.C., Weinman E.J. J. Biol. Chem. 274:24753-24758(1999) [PubMed: 10455146] [Abstract] Cited for: FUNCTION, INTERACTION WITH SLC9A3.
[10]	"Molecular requirements for the regulation of the renal outer medullary K(+) channel ROMK1 by the serum- and glucocorticoid-inducible kinase SGK1." Palmada M., Embark H.M., Yun C., Bohmer C., Lang F. Biochem. Biophys. Res. Commun. 311:629-634(2003) [PubMed: 14623317] [Abstract] Cited for: INTERACTION WITH SGK1 AND KCNJ1/ROMK1.
[11]	"NHERF2 specifically interacts with LPA2 receptor and defines the specificity and efficiency of receptor-mediated phospholipase C-beta3 activation." Oh Y.-S., Jo N.W., Choi J.W., Kim H.S., Seo S.-W., Kang K.-O., Hwang J.-I., Heo K., Kim S.-H., Kim Y.-H., Kim I.-H., Kim J.H., Banno Y., Ryu S.H., Suh P.-G. Mol. Cell. Biol. 24:5069-5079(2004) [PubMed: 15143197] [Abstract] Cited for: INTERACTION WITH LPAR2.
[12]	"Large-scale characterization of HeLa cell nuclear phosphoproteins." Beausoleil S.A., Jedrychowski M., Schwartz D., Elias J.E., Villen J., Li J., Cohn M.A., Cantley L.C., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 101:12130-12135(2004) [PubMed: 15302935] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-275, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[13]	"Gp135/podocalyxin and NHERF-2 participate in the formation of a preapical domain during polarization of MDCK cells." Meder D., Shevchenko A., Simons K., Fuellekrug J. J. Cell Biol. 168:303-313(2005) [PubMed: 15642748] [Abstract] Cited for: INTERACTION WITH PODXL.
[14]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-183 AND SER-254, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[15]	"MCC, a new interacting protein for Scrib, is required for cell migration in epithelial cells." Arnaud C., Sebbagh M., Nola S., Audebert S., Bidaut G., Hermant A., Gayet O., Dusetti N.J., Ollendorff V., Santoni M.J., Borg J.P., Lecine P. FEBS Lett. 583:2326-2332(2009) [PubMed: 19555689] [Abstract] Cited for: INTERACTION WITH MCC.
[16]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[17]	"Structural basis for NHERF recognition by ERM proteins." Terawaki S., Maesaki R., Hakoshima T. Structure 14:777-789(2006) [PubMed: 16615918] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.81 ANGSTROMS) OF 310-337 IN COMPLEX WITH RDX.
[18]	"The crystal structure of the first and second PDZ domain of human NHERF-2 (SLC9A3R2) interacting with a mode 1 PDZ binding motif." Structural genomics consortium (SGC) Submitted (JAN-2007) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 9-232.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U82108 mRNA. Translation: AAB53042.1.
Z50150 mRNA. Translation: CAA90511.1. Frameshift.
AF004900 mRNA. Translation: AAC63061.1.
AF035771 mRNA. Translation: AAC52090.1.
AB014460 Genomic DNA. Translation: BAA32696.1.
AB016243 Genomic DNA. Translation: BAA33216.1.
AC005600 Genomic DNA. Translation: AAC34208.1.
CH471112 Genomic DNA. Translation: EAW85563.1.
CH471112 Genomic DNA. Translation: EAW85564.1.
BC014513 mRNA. Translation: AAH14513.2. Different initiation.
BC106001 mRNA. Translation: AAI06002.1.

IPI

IPI00385034.
IPI00398293.

PIR

G01158.

RefSeq

NP_001123484.1. NM_001130012.2.
NP_004776.3. NM_004785.5.

UniGene

Hs.440896.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2D11	X-ray	2.81	E/F/G/H	310-337	[»]
2HE4	X-ray	1.45	A	147-228	[»]
2OCS	X-ray	1.50	A	9-91	[»]

ProteinModelPortal

Q15599.

SMR

Q15599. Positions 7-337.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29093N.

IntAct

Q15599. 9 interactions.

MINT

MINT-126664.

STRING

Q15599.

PTM databases

PhosphoSite

Q15599.

Polymorphism databases

DMDM

42559433.

Proteomic databases

PRIDE

Q15599.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000191922; ENSP00000191922; ENSG00000065054.
ENST00000424542; ENSP00000408005; ENSG00000065054.

GeneID

9351.

KEGG

hsa:9351.

UCSC

uc002coi.1. human.
uc002coj.1. human.

Organism-specific databases

CTD

9351.

GeneCards

GC16P002076.

H-InvDB

HIX0012710.

HGNC

HGNC:11076. SLC9A3R2.

HPA

HPA001672.

MIM

606553. gene.

neXtProt

NX_Q15599.

PharmGKB

PA35932.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG10978.

GeneTree

ENSGT00530000062999.

HOVERGEN

HBG052616.

InParanoid

Q15599.

OrthoDB

EOG4MPHR1.

Enzyme and pathway databases

Pathway_Interaction_DB

lysophospholipid_pathway. LPA receptor mediated events.
pdgfrbpathway. PDGFR-beta signaling pathway.

Gene expression databases

ArrayExpress

Q15599.

Bgee

Q15599.

CleanEx

HS_SLC9A3R2.

Genevestigator

Q15599.

GermOnline

ENSG00000065054. Homo sapiens.

Family and domain databases

InterPro

IPR015098. EBP50_C-term.
IPR017300. NaH_exchngr_reg_CF_NHE-RF.
IPR001478. PDZ/DHR/GLGF.
[Graphical view]

KO

K13358.

Pfam

PF09007. EBP50_C-term. 1 hit.
PF00595. PDZ. 2 hits.
[Graphical view]

PIRSF

PIRSF037866. EBP50. 1 hit.

ProDom

PD283022. EBP50_C-term. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00228. PDZ. 2 hits.
[Graphical view]

SUPFAM

SSF50156. PDZ. 2 hits.

PROSITE

PS50106. PDZ. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

NextBio

35017.

SOURCE

Search...

Entry information

Entry name

NHRF2_HUMAN

Accession

Primary (citable) accession number: Q15599
Secondary accession number(s): D3DU84 , O00272, O00556, Q3KQY7

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 16, 2004
Last sequence update:	February 16, 2004
Last modified:	January 25, 2012
This is version 115 of the entry and version 2 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.