ID SAV1_HUMAN Reviewed; 383 AA. AC Q9H4B6; A8K4B8; D3DSB6; Q6IA58; Q9H949; Q9HAK9; DT 11-JUL-2003, integrated into UniProtKB/Swiss-Prot. DT 11-JUL-2003, sequence version 2. DT 27-MAR-2024, entry version 175. DE RecName: Full=Protein salvador homolog 1; DE AltName: Full=45 kDa WW domain protein; DE Short=hWW45; GN Name=SAV1; Synonyms=WW45; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=11027580; DOI=10.1006/bbrc.2000.3582; RA Valverde P.; RT "Cloning, expression and mapping of hWW45, a novel WW-domain containing RT gene."; RL Biochem. Biophys. Res. Commun. 276:990-998(2000). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Fetus, and Neuron; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Kidney; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP INTERACTION WITH STK3/MST2. RX PubMed=15688006; DOI=10.1038/sj.onc.1208445; RA Chan E.H.Y., Nousiainen M., Chalamalasetty R.B., Schaefer A., Nigg E.A., RA Sillje H.H.W.; RT "The Ste20-like kinase Mst2 activates the human large tumor suppressor RT kinase Lats1."; RL Oncogene 24:2076-2086(2005). RN [7] RP FUNCTION, HOMODIMERIZATION, INTERACTION WITH STK3/MST2 AND STK4/MST1, AND RP PHOSPHORYLATION. RX PubMed=16930133; DOI=10.1111/j.1742-4658.2006.05427.x; RA Callus B.A., Verhagen A.M., Vaux D.L.; RT "Association of mammalian sterile twenty kinases, Mst1 and Mst2, with RT hSalvador via C-terminal coiled-coil domains, leads to its stabilization RT and phosphorylation."; RL FEBS J. 273:4264-4276(2006). RN [8] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [9] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH STK4/MST1, AND TISSUE RP SPECIFICITY. RX PubMed=19212654; RA Luo X., Li Z., Yan Q., Li X., Tao D., Wang J., Leng Y., Gardner K., RA Judge S.I., Li Q.Q., Hu J., Gong J.; RT "The human WW45 protein enhances MST1-mediated apoptosis in vivo."; RL Int. J. Mol. Med. 23:357-362(2009). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-210, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [11] RP INTERACTION WITH WTIP AND AJUBA. RX PubMed=20303269; DOI=10.1016/j.cub.2010.02.035; RA Das Thakur M., Feng Y., Jagannathan R., Seppa M.J., Skeath J.B., RA Longmore G.D.; RT "Ajuba LIM proteins are negative regulators of the Hippo signaling RT pathway."; RL Curr. Biol. 20:657-662(2010). RN [12] RP FUNCTION, AND INTERACTION WITH NEK2. RX PubMed=21076410; DOI=10.1038/ncb2120; RA Mardin B.R., Lange C., Baxter J.E., Hardy T., Scholz S.R., Fry A.M., RA Schiebel E.; RT "Components of the Hippo pathway cooperate with Nek2 kinase to regulate RT centrosome disjunction."; RL Nat. Cell Biol. 12:1166-1176(2010). RN [13] RP FUNCTION, AND INTERACTION WITH ESR1. RX PubMed=21104395; DOI=10.1007/s00109-010-0698-y; RA Park Y., Park J., Lee Y., Lim W., Oh B.C., Shin C., Kim W., Lee Y.; RT "Mammalian MST2 kinase and human Salvador activate and reduce estrogen RT receptor alpha in the absence of ligand."; RL J. Mol. Med. 89:181-191(2011). RN [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-94, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [15] RP INTERACTION WITH STK3. RX PubMed=28087714; DOI=10.1101/gad.284539.116; RA Kwan J., Sczaniecka A., Arash E.H., Nguyen L., Chen C.C., Ratkovic S., RA Klezovitch O., Attisano L., McNeill H., Emili A., Vasioukhin V.; RT "DLG5 connects cell polarity and Hippo signaling protein networks by RT linking PAR-1 with MST1/2."; RL Genes Dev. 30:2696-2709(2016). RN [16] RP VARIANT ASP-185. RX PubMed=12202036; DOI=10.1016/s0092-8674(02)00824-3; RA Tapon N., Harvey K.F., Bell D.W., Wahrer D.C.R., Schiripo T.A., Haber D.A., RA Hariharan I.K.; RT "Salvador promotes both cell cycle exit and apoptosis in Drosophila and is RT mutated in human cancer cell lines."; RL Cell 110:467-478(2002). CC -!- FUNCTION: Regulator of STK3/MST2 and STK4/MST1 in the Hippo signaling CC pathway which plays a pivotal role in organ size control and tumor CC suppression by restricting proliferation and promoting apoptosis. The CC core of this pathway is composed of a kinase cascade wherein STK3/MST2 CC and STK4/MST1, in complex with its regulatory protein SAV1, CC phosphorylates and activates LATS1/2 in complex with its regulatory CC protein MOB1, which in turn phosphorylates and inactivates YAP1 CC oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS1/2 inhibits CC its translocation into the nucleus to regulate cellular genes important CC for cell proliferation, cell death, and cell migration. SAV1 is CC required for STK3/MST2 and STK4/MST1 activation and promotes cell-cycle CC exit and terminal differentiation in developing epithelial tissues. CC Plays a role in centrosome disjunction by regulating the localization CC of NEK2 to centrosomes, and its ability to phosphorylate CROCC and CC CEP250. In conjunction with STK3/MST2, activates the transcriptional CC activity of ESR1 through the modulation of its phosphorylation. CC {ECO:0000269|PubMed:16930133, ECO:0000269|PubMed:19212654, CC ECO:0000269|PubMed:21076410, ECO:0000269|PubMed:21104395}. CC -!- SUBUNIT: Homodimer. Stabilized through interaction with STK3/MST2 or CC STK4/MST1. Interacts (via SARAH domain) with isoform 1 of NEK2. CC Interacts with ESR1 only in the presence of STK3/MST2. Interacts with CC WTIP and AJUBA. {ECO:0000269|PubMed:15688006, CC ECO:0000269|PubMed:16930133, ECO:0000269|PubMed:19212654, CC ECO:0000269|PubMed:20303269, ECO:0000269|PubMed:21076410, CC ECO:0000269|PubMed:21104395, ECO:0000269|PubMed:28087714}. CC -!- INTERACTION: CC Q9H4B6; O00165: HAX1; NbExp=7; IntAct=EBI-1017775, EBI-357001; CC Q9H4B6; Q9H4B6: SAV1; NbExp=2; IntAct=EBI-1017775, EBI-1017775; CC Q9H4B6; Q13188: STK3; NbExp=26; IntAct=EBI-1017775, EBI-992580; CC Q9H4B6; Q13043: STK4; NbExp=19; IntAct=EBI-1017775, EBI-367376; CC Q9H4B6; Q13043-1: STK4; NbExp=2; IntAct=EBI-1017775, EBI-15638366; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:19212654}. Cytoplasm CC {ECO:0000269|PubMed:19212654}. CC -!- TISSUE SPECIFICITY: Ubiquitously expressed in adult tissues with CC highest expression in the pancreas, aorta and interventricular septum CC and lowest expression in skeletal muscle. Expression was higher in CC fetal than in the adult heart. Expressed in various cell lines. CC {ECO:0000269|PubMed:19212654}. CC -!- PTM: Phosphorylated by STK3/MST2 and STK4/MST1. Phosphorylation is not CC required for SAV1 stability and may increase the number of protein CC binding sites on the scaffold molecule. {ECO:0000269|PubMed:16930133}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/42206/SAV1"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AJ292969; CAC13972.1; -; mRNA. DR EMBL; AK021500; BAB13835.1; -; mRNA. DR EMBL; AK023071; BAB14390.1; -; mRNA. DR EMBL; AK290883; BAF83572.1; -; mRNA. DR EMBL; CR457297; CAG33578.1; -; mRNA. DR EMBL; CH471078; EAW65702.1; -; Genomic_DNA. DR EMBL; CH471078; EAW65704.1; -; Genomic_DNA. DR EMBL; BC020537; AAH20537.1; -; mRNA. DR CCDS; CCDS9701.1; -. DR PIR; JC7507; JC7507. DR RefSeq; NP_068590.1; NM_021818.3. DR PDB; 6AO5; X-ray; 2.96 A; B=291-383. DR PDBsum; 6AO5; -. DR AlphaFoldDB; Q9H4B6; -. DR SMR; Q9H4B6; -. DR BioGRID; 121917; 176. DR CORUM; Q9H4B6; -. DR DIP; DIP-36127N; -. DR IntAct; Q9H4B6; 99. DR MINT; Q9H4B6; -. DR STRING; 9606.ENSP00000324729; -. DR iPTMnet; Q9H4B6; -. DR PhosphoSitePlus; Q9H4B6; -. DR BioMuta; SAV1; -. DR DMDM; 32699681; -. DR EPD; Q9H4B6; -. DR jPOST; Q9H4B6; -. DR MassIVE; Q9H4B6; -. DR MaxQB; Q9H4B6; -. DR PaxDb; 9606-ENSP00000324729; -. DR PeptideAtlas; Q9H4B6; -. DR ProteomicsDB; 80818; -. DR Pumba; Q9H4B6; -. DR Antibodypedia; 23683; 289 antibodies from 27 providers. DR DNASU; 60485; -. DR Ensembl; ENST00000324679.5; ENSP00000324729.4; ENSG00000151748.15. DR GeneID; 60485; -. DR KEGG; hsa:60485; -. DR MANE-Select; ENST00000324679.5; ENSP00000324729.4; NM_021818.4; NP_068590.1. DR UCSC; uc001wyh.3; human. DR AGR; HGNC:17795; -. DR CTD; 60485; -. DR DisGeNET; 60485; -. DR GeneCards; SAV1; -. DR HGNC; HGNC:17795; SAV1. DR HPA; ENSG00000151748; Low tissue specificity. DR MIM; 607203; gene. DR neXtProt; NX_Q9H4B6; -. DR OpenTargets; ENSG00000151748; -. DR PharmGKB; PA134875018; -. DR VEuPathDB; HostDB:ENSG00000151748; -. DR eggNOG; KOG1891; Eukaryota. DR GeneTree; ENSGT00940000156106; -. DR HOGENOM; CLU_060422_0_0_1; -. DR InParanoid; Q9H4B6; -. DR OMA; AARYYYP; -. DR OrthoDB; 3673987at2759; -. DR PhylomeDB; Q9H4B6; -. DR TreeFam; TF317631; -. DR PathwayCommons; Q9H4B6; -. DR Reactome; R-HSA-2028269; Signaling by Hippo. DR SignaLink; Q9H4B6; -. DR SIGNOR; Q9H4B6; -. DR BioGRID-ORCS; 60485; 21 hits in 1170 CRISPR screens. DR ChiTaRS; SAV1; human. DR GeneWiki; SAV1; -. DR GenomeRNAi; 60485; -. DR Pharos; Q9H4B6; Tbio. DR PRO; PR:Q9H4B6; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; Q9H4B6; Protein. DR Bgee; ENSG00000151748; Expressed in oocyte and 196 other cell types or tissues. DR ExpressionAtlas; Q9H4B6; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0060090; F:molecular adaptor activity; IBA:GO_Central. DR GO; GO:0060038; P:cardiac muscle cell proliferation; IEA:Ensembl. DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl. DR GO; GO:0001942; P:hair follicle development; IEA:Ensembl. DR GO; GO:0035329; P:hippo signaling; ISS:UniProtKB. DR GO; GO:0060575; P:intestinal epithelial cell differentiation; IEA:Ensembl. DR GO; GO:0097283; P:keratinocyte apoptotic process; IEA:Ensembl. DR GO; GO:0030216; P:keratinocyte differentiation; IEA:Ensembl. DR GO; GO:0060487; P:lung epithelial cell differentiation; IEA:Ensembl. DR GO; GO:0060044; P:negative regulation of cardiac muscle cell proliferation; IEA:Ensembl. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IBA:GO_Central. DR GO; GO:0050680; P:negative regulation of epithelial cell proliferation; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IBA:GO_Central. DR GO; GO:0045600; P:positive regulation of fat cell differentiation; IEA:Ensembl. DR GO; GO:1902174; P:positive regulation of keratinocyte apoptotic process; IEA:Ensembl. DR GO; GO:0050821; P:protein stabilization; IEA:Ensembl. DR GO; GO:2000036; P:regulation of stem cell population maintenance; IEA:Ensembl. DR GO; GO:0060412; P:ventricular septum morphogenesis; IEA:Ensembl. DR CDD; cd21433; SARAH_Sav; 1. DR CDD; cd00201; WW; 2. DR Gene3D; 2.20.70.10; -; 2. DR InterPro; IPR011524; SARAH_dom. DR InterPro; IPR030030; Sav. DR InterPro; IPR001202; WW_dom. DR InterPro; IPR036020; WW_dom_sf. DR PANTHER; PTHR47522:SF2; PROTEIN SALVADOR HOMOLOG 1; 1. DR PANTHER; PTHR47522; SALVADOR FAMILY WW DOMAIN-CONTAINING PROTEIN 1; 1. DR Pfam; PF00397; WW; 1. DR SMART; SM00456; WW; 2. DR SUPFAM; SSF51045; WW domain; 2. DR PROSITE; PS50951; SARAH; 1. DR PROSITE; PS50020; WW_DOMAIN_2; 2. DR Genevisible; Q9H4B6; HS. PE 1: Evidence at protein level; KW 3D-structure; Coiled coil; Cytoplasm; Nucleus; Phosphoprotein; KW Reference proteome; Repeat. FT CHAIN 1..383 FT /note="Protein salvador homolog 1" FT /id="PRO_0000076060" FT DOMAIN 199..232 FT /note="WW 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT DOMAIN 234..267 FT /note="WW 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT DOMAIN 321..368 FT /note="SARAH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00310" FT COILED 344..373 FT /evidence="ECO:0000255" FT MOD_RES 94 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 136 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8VEB2" FT MOD_RES 210 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:19369195" FT VARIANT 185 FT /note="A -> D (in a colon cancer cell line)" FT /evidence="ECO:0000269|PubMed:12202036" FT /id="VAR_015880" FT CONFLICT 5 FT /note="K -> Q (in Ref. 1; CAC13972)" FT /evidence="ECO:0000305" FT CONFLICT 18 FT /note="Q -> R (in Ref. 3; CAG33578)" FT /evidence="ECO:0000305" FT CONFLICT 292 FT /note="L -> F (in Ref. 2; BAB13835)" FT /evidence="ECO:0000305" FT HELIX 298..300 FT /evidence="ECO:0007829|PDB:6AO5" FT HELIX 306..313 FT /evidence="ECO:0007829|PDB:6AO5" FT STRAND 316..319 FT /evidence="ECO:0007829|PDB:6AO5" FT HELIX 329..375 FT /evidence="ECO:0007829|PDB:6AO5" SQ SEQUENCE 383 AA; 44634 MW; 4012C40A8601417A CRC64; MLSRKKTKNE VSKPAEVQGK YVKKETSPLL RNLMPSFIRH GPTIPRRTDI CLPDSSPNAF STSGDVVSRN QSFLRTPIQR TPHEIMRRES NRLSAPSYLA RSLADVPREY GSSQSFVTEV SFAVENGDSG SRYYYSDNFF DGQRKRPLGD RAHEDYRYYE YNHDLFQRMP QNQGRHASGI GRVAATSLGN LTNHGSEDLP LPPGWSVDWT MRGRKYYIDH NTNTTHWSHP LEREGLPPGW ERVESSEFGT YYVDHTNKKA QYRHPCAPSV PRYDQPPPVT YQPQQTERNQ SLLVPANPYH TAEIPDWLQV YARAPVKYDH ILKWELFQLA DLDTYQGMLK LLFMKELEQI VKMYEAYRQA LLTELENRKQ RQQWYAQQHG KNF //