SAV1 (Salvador homolog 1 (Drosophila))

2007-06-01   Bernard A Callus 

Biochemistry Department, La Trobe University, Bundoora VIC 3086, Australia

Identity

HGNC
LOCATION
14q22.1
LOCUSID
ALIAS
SAV,WW45,WWP4
FUSION GENES

DNA/RNA

Atlas Image
SAV1 is encoded by five exons represented by the boxes. The blue shaded region indicates the Sav1 coding region while the untranslated regions (UTR) are shown in white.

Description

The Sav1 gene spans 34.7 kb.

Transcription

The longest SAV1 mRNA transcript of 3.0 kb encodes an open reading frame (ORF) of 1152 bases and untranslated regions of 338 and 1541 bases at the 5 and 3 ends, respectively. No splice variants have been reported for SAV1. Smaller transcripts of 1.8 kb and 2.1 kb, encoding the identical ORF, have been isolated which may be the result of alternative sites of poly-adenylation.

Proteins

Atlas Image
SAV1 contains two central proline-binding WW domains (red) and a C-terminal SARAH (for Salvador/Rassf/Hippo) domain (green).

Description

Sav1 is 383 amino acids in length with an expected weight of 44,606 Da. WW1: residues 199-232; WW2: 234-267; SARAH domain: residues 321-368. The SARAH domain partially overlaps with a predicted coiled-coil domain: 344-373.

Expression

SAV1 mRNA is ubiquitously expressed in adult tissues with highest expression in the placenta, pancreas, heart, kidney, lung and aorta and lowest expression in skeletal muscle. Expression was higher in fetal heart compared with adult heart.

Localisation

SAV1 is localized to the centrosome during interphase and metaphase and localizes with the contractile ring during cytokinesis. SAV1 co-localizes with MST2, RASSF1A and LATS1 during anaphase, interphase, metaphase and cytokinesis.

Function

Sav1 is a scaffold protein and able to homodimerize independently of its SARAH domain. Sav1 binds to MST1/2 kinases and RASSF1A in an interaction that requires their homologous SARAH domains. The binding of MST stabilizes SAV1 abundance and enhances the association of SAV1 with RASSF1A. SAV1 is phosphorylated by MST1/2 but the consequence of this is not known. The MST2/SAV1/RASSF1A complex can recruit LATS1 kinase resulting in the activation of LATS1 by MST2. The MST2/SAV1/RASSF1A/LATS1 complex may function in regulating cell-cycle exit. In Drosophila, dSav mutant tissue is more resistant to apoptosis and grows more quickly compared with wild type tissue suggesting dSav is a dual regulator of cell proliferation and apoptosis.

Homology

mSav1 is 94% identical to hSav1. hSav1 is 31% identical and 44% similar to dSav from Drosophila melanogaster, however, the similarity increases to 59% if only the sequences comprising the WW and SARAH domains are compared. There is no recognizable orthologue of hSav1 in S.cerevisiae.

Mutations

Note

The cDNA sequence for SAV1 is conflicted at codons 5 (K/Q), 18 (Q/R), 292 (L/F) and 373 (Q/stop).

Germinal

No germline mutations for SAV1 have been reported.

Somatic

In one study of 52 cancer cell lines, SAV1 was deleted in two renal cancer cell lines (ACHN and 786-O) and a C to A mutation at nucleotide 554 (Ala185Asp) was detected in a colon cancer cell line (HCT15). A second study from the Korean population failed to detect the C554A polymorphism or any additional mutations of SAV1 in 324 cancer cell lines. A third study failed to detect hypermethylation the SAV1 promoter in 44 soft tissue sarcomas and 6 sarcoma cell lines. These results suggest that (1) the C554A mutation found in the colon cancer cell line might be a true mutation and (2) that SAV1 is not frequently mutated in human cancers.

Implicated in

Entity name
To date SAV1 is not implicated in any diseases.

Bibliography

Pubmed IDLast YearTitleAuthors
169301332006Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation.Callus BA et al
156880062005The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1.Chan EH et al
173795202007RASSF1A is part of a complex similar to the Drosophila Hippo/Salvador/Lats tumor-suppressor network.Guo C et al
147020392004Complete sequencing and characterization of 21,243 full-length human cDNAs.Ota T et al
175389462007Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma.Seidel C et al
124779322002Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.Strausberg RL et al
93731491997Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library.Suzuki Y et al
122020362002salvador Promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines.Tapon N et al
110275802000Cloning, expression, and mapping of hWW45, a novel human WW domain-containing gene.Valverde P et al
129690142003Mutational analysis of salvador gene in human carcinomas.Yoo NJ et al

Other Information

Locus ID:

NCBI: 60485
MIM: 607203
HGNC: 17795
Ensembl: ENSG00000151748

Variants:

dbSNP: 60485
ClinVar: 60485
TCGA: ENSG00000151748
COSMIC: SAV1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000151748ENST00000324679Q9H4B6
ENSG00000151748ENST00000553731H0YJ02
ENSG00000151748ENST00000555720H0YJH0
ENSG00000151748ENST00000556735G3V453
ENSG00000151748ENST00000557458H0YJT4

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45
50

Pathways

PathwaySourceExternal ID
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
Hippo signalingKEGGhsa_M00683
Hippo signalingKEGGM00683
Signal TransductionREACTOMER-HSA-162582
Signaling by HippoREACTOMER-HSA-2028269
Hippo signaling pathway -multiple speciesKEGGko04392
Hippo signaling pathway -multiple speciesKEGGhsa04392

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
169301332006Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation.89
210764102010Components of the Hippo pathway cooperate with Nek2 kinase to regulate centrosome disjunction.78
221853432011Downregulation of SAV1 plays a role in pathogenesis of high-grade clear cell renal cell carcinoma.27
253672212014The MST1/2-SAV1 complex of the Hippo pathway promotes ciliogenesis.27
290638332017SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK.25
214899912011Salvador protein is a tumor suppressor effector of RASSF1A with hippo pathway-independent functions.20
215670722011hSav1 interacts with HAX1 and attenuates its anti-apoptotic effects in MCF-7 breast cancer cells.10
286184502017SAV1 represses the development of human colorectal cancer by regulating the Akt-mTOR pathway in a YAP-dependent manner.7
295198172018Salvador has an extended SARAH domain that mediates binding to Hippo kinase.6
276611232016WW45, a Gli1 binding protein, negatively regulated Hedgehog signaling in lung cancer.5

Citation

Bernard A Callus

SAV1 (Salvador homolog 1 (Drosophila))

Atlas Genet Cytogenet Oncol Haematol. 2007-06-01

Online version: http://atlasgeneticsoncology.org/gene/42206/sav1