Q9H4B6 (SAV1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Protein salvador homolog 1

Alternative name(s):
45 kDa WW domain protein
Short name=hWW45

Gene names

Name:	SAV1
Synonyms:	WW45

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 › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	383 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Regulator of STK3/MST2 and STK4/MST1 in the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. SAV1 is required for STK3/MST2 and STK4/MST1 activation and promotes cell-cycle exit and terminal differentiation in developing epithelial tissues. Plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosomes, and its ability to phosphorylate CROCC and CEP250. In conjunction with STK3/MST2, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation. Ref.7 Ref.9 Ref.12 Ref.13
Subunit structure	Homodimer. Stabilized through interaction with STK3/MST2 or STK4/MST1. Interacts (via SARAH domain) with isoform 1of NEK2. Interacts with ESR1 only in the presence of STK3/MST2. Interacts with WTIP and AJUBA. Ref.6 Ref.7 Ref.9 Ref.11 Ref.12 Ref.13
Subcellular location	Nucleus. Cytoplasm Ref.9.
Tissue specificity	Ubiquitously expressed in adult tissues with highest expression in the pancreas, aorta and interventricular septum and lowest expression in skeletal muscle. Expression was higher in fetal than in the adult heart. Expressed in various cell lines. Ref.9
Post-translational modification	Phosphorylated by STK3/MST2 and STK4/MST1. Phosphorylation is not required for SAV1 stability and may increase the number of protein binding sites on the scaffold molecule. Ref.7
Sequence similarities	Contains 1 SARAH domain. Contains 2 WW domains.

Ontologies

Keywords
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Domain	Coiled coil Repeat
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	hair follicle development Inferred from electronic annotation. Source: Ensembl hippo signaling Inferred from sequence or structural similarity. Source: UniProtKB intestinal epithelial cell differentiation Inferred from electronic annotation. Source: Ensembl keratinocyte differentiation Inferred from electronic annotation. Source: Ensembl lung epithelial cell differentiation Inferred from electronic annotation. Source: Ensembl negative regulation of cardiac muscle cell proliferation Inferred from electronic annotation. Source: Ensembl negative regulation of epithelial cell proliferation Inferred from electronic annotation. Source: Ensembl positive regulation of apoptotic process Inferred from electronic annotation. Source: Ensembl regulation of stem cell maintenance Inferred from electronic annotation. Source: Ensembl ventricular septum morphogenesis Inferred from electronic annotation. Source: Ensembl
Cellular_component	cytoplasm Inferred from direct assay Ref.9. Source: UniProtKB cytosol Traceable author statement. Source: Reactome nucleus Inferred from direct assay Ref.9. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
STK3	Q13188	15	EBI-1017775,EBI-992580
STK4	Q13043	16	EBI-1017775,EBI-367376

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 383	383	Protein salvador homolog 1		PRO_0000076060
Regions
	Domain	199 – 232	34	WW 1
	Domain	234 – 267	34	WW 2
	Domain	321 – 368	48	SARAH
	Coiled coil	344 – 373	30	Potential
Amino acid modifications
	Modified residue	210	1	Phosphothreonine Ref.10
Natural variations
	Natural variant	185	1	A → D in a colon cancer cell line. Ref.14		VAR_015880
Experimental info
	Sequence conflict	5	1	K → Q in CAC13972. Ref.1
	Sequence conflict	18	1	Q → R in CAG33578. Ref.3
	Sequence conflict	292	1	L → F in BAB13835. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q9H4B6 [UniParc]. Last modified July 11, 2003. Version 2. Checksum: 4012C40A8601417A	FASTA	383	44,634
	10 20 30 40 50 60 MLSRKKTKNE VSKPAEVQGK YVKKETSPLL RNLMPSFIRH GPTIPRRTDI CLPDSSPNAF 70 80 90 100 110 120 STSGDVVSRN QSFLRTPIQR TPHEIMRRES NRLSAPSYLA RSLADVPREY GSSQSFVTEV 130 140 150 160 170 180 SFAVENGDSG SRYYYSDNFF DGQRKRPLGD RAHEDYRYYE YNHDLFQRMP QNQGRHASGI 190 200 210 220 230 240 GRVAATSLGN LTNHGSEDLP LPPGWSVDWT MRGRKYYIDH NTNTTHWSHP LEREGLPPGW 250 260 270 280 290 300 ERVESSEFGT YYVDHTNKKA QYRHPCAPSV PRYDQPPPVT YQPQQTERNQ SLLVPANPYH 310 320 330 340 350 360 TAEIPDWLQV YARAPVKYDH ILKWELFQLA DLDTYQGMLK LLFMKELEQI VKMYEAYRQA 370 380 LLTELENRKQ RQQWYAQQHG KNF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning, expression and mapping of hWW45, a novel WW-domain containing gene." Valverde P. Biochem. Biophys. Res. Commun. 276:990-998(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"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]. Tissue: Fetus and Neuron.
[3]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]	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].
[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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Kidney.
[6]	"The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1." Chan E.H.Y., Nousiainen M., Chalamalasetty R.B., Schaefer A., Nigg E.A., Sillje H.H.W. Oncogene 24:2076-2086(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH STK3/MST2.
[7]	"Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation." Callus B.A., Verhagen A.M., Vaux D.L. FEBS J. 273:4264-4276(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, HOMODIMERIZATION, INTERACTION WITH STK3/MST2 AND STK4/MST1, PHOSPHORYLATION.
[8]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[9]	"The human WW45 protein enhances MST1-mediated apoptosis in vivo." Luo X., Li Z., Yan Q., Li X., Tao D., Wang J., Leng Y., Gardner K., Judge S.I., Li Q.Q., Hu J., Gong J. Int. J. Mol. Med. 23:357-362(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH STK4/MST1, TISSUE SPECIFICITY.
[10]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-210, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[11]	"Ajuba LIM proteins are negative regulators of the Hippo signaling pathway." Das Thakur M., Feng Y., Jagannathan R., Seppa M.J., Skeath J.B., Longmore G.D. Curr. Biol. 20:657-662(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH WTIP AND AJUBA.
[12]	"Components of the Hippo pathway cooperate with Nek2 kinase to regulate centrosome disjunction." Mardin B.R., Lange C., Baxter J.E., Hardy T., Scholz S.R., Fry A.M., Schiebel E. Nat. Cell Biol. 12:1166-1176(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH NEK2.
[13]	"Mammalian MST2 kinase and human Salvador activate and reduce estrogen receptor alpha in the absence of ligand." Park Y., Park J., Lee Y., Lim W., Oh B.C., Shin C., Kim W., Lee Y. J. Mol. Med. 89:181-191(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH ESR1.
[14]	"Salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines." Tapon N., Harvey K.F., Bell D.W., Wahrer D.C.R., Schiripo T.A., Haber D.A., Hariharan I.K. Cell 110:467-478(2002) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ASP-185.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases
EMBL GenBank DDBJ	AJ292969 mRNA. Translation: CAC13972.1. AK021500 mRNA. Translation: BAB13835.1. AK023071 mRNA. Translation: BAB14390.1. AK290883 mRNA. Translation: BAF83572.1. CR457297 mRNA. Translation: CAG33578.1. CH471078 Genomic DNA. Translation: EAW65702.1. CH471078 Genomic DNA. Translation: EAW65704.1. BC020537 mRNA. Translation: AAH20537.1.
PIR	JC7507.
RefSeq	NP_068590.1. NM_021818.3.
UniGene	Hs.642842. Hs.706933.
3D structure databases
ProteinModelPortal	Q9H4B6.
SMR	Q9H4B6. Positions 197-269.
ModBase	Search...
MobiDB	Search...
Protein-protein interaction databases
BioGrid	121917. 57 interactions.
IntAct	Q9H4B6. 60 interactions.
MINT	MINT-2817789.
STRING	9606.ENSP00000324729.
PTM databases
PhosphoSite	Q9H4B6.
Polymorphism databases
DMDM	32699681.
Proteomic databases
PaxDb	Q9H4B6.
PRIDE	Q9H4B6.
Protocols and materials databases
DNASU	60485.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000324679; ENSP00000324729; ENSG00000151748.
GeneID	60485.
KEGG	hsa:60485.
UCSC	uc001wyh.2. human.
Organism-specific databases
CTD	60485.
GeneCards	GC14M051100.
HGNC	HGNC:17795. SAV1.
HPA	HPA001808.
MIM	607203. gene.
neXtProt	NX_Q9H4B6.
PharmGKB	PA134875018.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG314596.
HOGENOM	HOG000013074.
HOVERGEN	HBG044514.
InParanoid	Q9H4B6.
KO	K16686.
OMA	NKRAQYR.
PhylomeDB	Q9H4B6.
TreeFam	TF317631.
Enzyme and pathway databases
Reactome	REACT_111102. Signal Transduction.
SignaLink	Q9H4B6.
Gene expression databases
ArrayExpress	Q9H4B6.
Bgee	Q9H4B6.
CleanEx	HS_SAV1.
Genevestigator	Q9H4B6.
Family and domain databases
InterPro	IPR011524. SARAH_dom. IPR001202. WW_dom. [Graphical view]
Pfam	PF00397. WW. 1 hit. [Graphical view]
SMART	SM00456. WW. 2 hits. [Graphical view]
SUPFAM	SSF51045. SSF51045. 2 hits.
PROSITE	PS50951. SARAH. 1 hit. PS50020. WW_DOMAIN_2. 2 hits. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	SAV1. human.
GeneWiki	SAV1.
GenomeRNAi	60485.
NextBio	65363.
PRO	Q9H4B6.
SOURCE	Search...

Entry information

Entry name

SAV1_HUMAN

Accession

Primary (citable) accession number: Q9H4B6
Secondary accession number(s): A8K4B8 , D3DSB6, Q6IA58, Q9H949, Q9HAK9

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 11, 2003
Last sequence update:	July 11, 2003
Last modified:	April 16, 2014
This is version 101 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.