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SASH1 (SAM and SH3 domain containing 1)

Written2013-08Klaus-Peter Janssen
Department of Surgery, Technische Universitaet Muenchen, Ismaninger Str 22, 81675 Munich, Germany

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)KIAA0790
dJ323M4.1
SH3D6A
Other aliasdJ323M4
HGNC (Hugo) SASH1
LocusID (NCBI) 23328
Atlas_Id 43799
Location 6q24.3  [Link to chromosome band 6q24]
Location_base_pair Starts at 148272276 and ends at 148552050 bp from pter ( according to hg19-Feb_2009)  [Mapping SASH1.png]
Fusion genes
(updated 2016)
BTBD3 (20p12.2) / SASH1 (6q24.3)MLLT4 (6q27) / SASH1 (6q24.3)OXSR1 (3p22.2) / SASH1 (6q24.3)
PKD2 (4q22.1) / SASH1 (6q24.3)SAMD5 (6q24.3) / SASH1 (6q24.3)SASH1 (6q24.3) / ARID1B (6q25.3)
SASH1 (6q24.3) / DPF3 (14q24.2)SASH1 (6q24.3) / MLLT4 (6q27)SASH1 (6q24.3) / SAMD5 (6q24.3)

DNA/RNA

Note Entrez Gene: 23328 C, Ensembl: ENSG00000111961 C, UCSC: uc003qme.1 D, Vega:OTTHUMG00000015773.
 
  Schematic Structure of the Exon structure of human SASH1, as compared to the other members of the SLY-family of signal-adapter proteins, SLy1 (SH3-protein expressed in lymphocytes), and SAMSN1 (or SLy2). At the bottom, the transcribed full-length protein is shown schematically. SASH1 is the largest member of the protein family, it is encoded by 20 exons. All SLY-family proteins share a central conserved NLS (nuclear localisation signal) sequence, a SH3 and a SAM domain (dotted line). SASH1 comprises, in addition, a coiled-coil (CC) motif, a N-terminally located NLS signal (NLS2), a poly-prolin motif (PPP), and a second SAM domain at the C-terminus.
Description SASH1: located on human chromosome 6. Detailed gene locus: 6q24.3: 148593440-148873186 (forward strand).
ENSEMBL Database: Gene ID: ENSG00000111961.
Transcription 20 Protein-coding transcribed Exons, 7700 bp transcript, encoding 1247 amino acid residues.
Pseudogene No known pseudogenes.

Protein

Note Human SASH1 is comprised of 1247 amino acid residues, with a pI of 5.7, and a molecular mass of 137 kDa (please note that the apparent mass on denaturing SDS-PAGE is higher, roughly 170 kDa). SASH1 contains the following domains (from amino- to carboxyterminus): a predicted short coiled-coil stretch (CC), two predicted nuclear localisation signals (NLS1 and NLS2), a Src-homology-3 domain (SH3, aa 557 - aa 614), a first sterile alpha motif (SAM1, aa 633 - aa 697), a proline-rich sequence (PPP, aa 978 - aa 1059), and a second sterile alpha motif domain (SAM2, aa 1177 - aa 1241).
 
  Diagram schematically depicts human SASH1 protein (1247 aa), and the above-mentioned sequence-features: coiled-coil stretch (CC), nuclear localisation signals (NLS1 and NLS2), Src-homology-3 domain (SH3), a sterile alpha motif (SAM), a proline-rich sequence (PPP).
Description Human SASH1 was first described in 2003 as putative tumor suppressor in breast cancer, it encodes a protein with both cytosolic and nuclear localisation. It lacks enzymatic activity, but, due to its multiple protein-protein interactions domains (SH3, SAM, poly-prolin stretches), it is likely to serve as a signal-adapter module that integrates and coordinates other proteins, thereby acting as a negative/positive signal transduction nodule.
Expression SASH1 shows broad expression on protein level in human tissue and cell lines, as well as in mouse tissue. Exception: no or only weak expression has been found in lymphocytes.
Localisation SASH1 is found both in the cytosol, as well as in the nucleus, with the exception of the nucleolus. Enrichment in membrane-proximal areas in migrating cells at the lamellipodia (Martini et al., 2011).
Function SASH1 has no intrinsic enzyme activity, but can form multi-protein complexes due to its protein-protein interaction domains, and can modulate intracellular signal transduction. Moreover, SASH1 is implicated in the regulation of cell adhesion and migration (Martini et al., 2011).
Homology SASH1 belongs to the SLY-family, closest homologues: SLy1 and SLy2 (SH3-domain containing protein expressed in lymphocytes). Of note, SLy1 and SLy2 are much smaller (around 380 aa), and SLy1 is exclusively expressed in lymphocytes.

Mutations

Germinal Heterozygous germline mutations have been identified in the three nonconsanguineous families with benign dermatologic features in a Chinese study (Zhou et al., 2013). However, no correlation between these mutations and occurrence of malignoma has been reported so far:
1) T → G substitution at nucleotide 2126 (TAC → GAC) in exon 14, resulting in amino acid substitutions of Tyr to Asp (Y551D) at codon 551
2) T → C substitution at nucleotide 2019 (CTC → CCC) in exon 13, resulting in Leu to Pro at codon 515 (L515P)
3) G → A substitution (GAA → AAA) at position 2000 in exon 13, causing Glu to Lys at codon 509 (E509K).
Somatic No truncating or nonsense mutations have been identified in somatic cells for SASH1 in a study on human breast cancer (Zeller et al., 2003).

Implicated in

Note
  
Entity Breast cancer
Note Loss of the gene-internal microsatellite DNA marker D6S311 was found in 30% of samples of primary breast carcinoma, and the LOH was significantly correlated with poor survival and increase in tumor size. In established human mammary cancer cell lines, SASH1 is expressed at relatively low levels. SASH1 is downregulated in the majority (74%) of breast tumors in comparison with corresponding normal breast epithelia. In addition, SASH1 is also downregulated in tumors of the lung and thyroid. (Zeller et al., 2003).
  
  
Entity Colorectal cancer
Note The mRNA as well as protein expression of SASH1 was strongly and significantly reduced in colon cancer of UICC stage II, III, and IV, as well as in colorectal liver metastases. In contrast, SASH1 expression was not significantly altered in benign adenomas and in early stage lesions (UICC I). Around 40% of primary colon tumours tested (n=113) showed a 10-fold or stronger reduction in SASH1 expression, compared to normal colon mucosa. Decreased SASH1 mRNA expression was correlated with the occurrence of metachronous distant metastasis, and multivariate analysis identified SASH1 downregulation as an independent negative prognostic parameter for patient survival (Rimkus et al., 2006). Recently, these results were confirmed on an independent patient collective of stage II colon cancer (n=179 patients), confirming that decreased SASH1 expression is an independent negative prognostic factor in colon cancer, allowing to distinguish high-risk patients in early, locally restriced stages of the disease (Nitsche et al., 2012).
  
  
Entity Pancreatic cancer (unpublished observations)
Note In a collective of n=103 patients with pancreatic ductal adenocarcinoma, 38% of the tumors showed no or strongly reduced SASH1 protein expression by immunohistochemistry. Decreased SASH1 expression was significantly reduced with poor survival in Kaplan-Meier analysis (Tiago de Oliveira and Klaus-Peter Janssen, unpublished data).
  
  
Entity Benign dyskeratosis
Note SASH1 germline mutations have been identified in patients with a kind of dyschromatosis. Of note, three independent heterozygous germline mutations have been identified, that cause amino acid substitutions in the central SH3/SAM-containing region in the SASH1 gene. In epidermal tissues from an affected individual, increased transepithelial migration of melanocytes was observed (Zhou et al., 2013).
  
  
Entity Osteosarcoma
Note SASH1 protein was significantly down-regulated in osteosarcoma tissues compared to normal bone tissue. Moreover, SASH1 protein showed significant down-regulation in osteosarcoma tissues from patients with lung metastasis compared to those without lung metastasis, and, lastly, a gradual decrease of SASH1 expression occurred with increasing Enneking stage (Meng et al., 2013).
  

Bibliography

Effects of SASH1 on lung cancer cell proliferation, apoptosis, and invasion in vitro.
Chen EG, Chen Y, Dong LL, Zhang JS.
Tumour Biol. 2012 Oct;33(5):1393-401. doi: 10.1007/s13277-012-0387-2. Epub 2012 Apr 10.
PMID 22488244
 
Effects of SASH1 on melanoma cell proliferation and apoptosis in vitro.
Lin S, Zhang J, Xu J, Wang H, Sang Q, Xing Q, He L.
Mol Med Rep. 2012 Dec;6(6):1243-8. doi: 10.3892/mmr.2012.1099. Epub 2012 Sep 26.
PMID 23023727
 
The candidate tumor suppressor SASH1 interacts with the actin cytoskeleton and stimulates cell-matrix adhesion.
Martini M, Gnann A, Scheikl D, Holzmann B, Janssen KP.
Int J Biochem Cell Biol. 2011 Nov;43(11):1630-40. doi: 10.1016/j.biocel.2011.07.012. Epub 2011 Jul 28.
PMID 21820526
 
SASH1 regulates proliferation, apoptosis, and invasion of osteosarcoma cell.
Meng Q, Zheng M, Liu H, Song C, Zhang W, Yan J, Qin L, Liu X.
Mol Cell Biochem. 2013 Jan;373(1-2):201-10. doi: 10.1007/s11010-012-1491-8. Epub 2012 Oct 29.
PMID 23108792
 
Integrative marker analysis allows risk assessment for metastasis in stage II colon cancer.
Nitsche U, Rosenberg R, Balmert A, Schuster T, Slotta-Huspenina J, Herrmann P, Bader FG, Friess H, Schlag PM, Stein U, Janssen KP.
Ann Surg. 2012 Nov;256(5):763-71; discussion 771. doi: 10.1097/SLA.0b013e318272de87.
PMID 23095620
 
Prognostic significance of downregulated expression of the candidate tumour suppressor gene SASH1 in colon cancer.
Rimkus C, Martini M, Friederichs J, Rosenberg R, Doll D, Siewert JR, Holzmann B, Janssen KP.
Br J Cancer. 2006 Nov 20;95(10):1419-23. Epub 2006 Oct 31.
PMID 17088907
 
Overexpression of SASH1 related to the decreased invasion ability of human glioma U251 cells.
Yang L, Liu M, Gu Z, Chen J, Yan Y, Li J.
Tumour Biol. 2012 Dec;33(6):2255-63. doi: 10.1007/s13277-012-0487-z. Epub 2012 Aug 23.
PMID 22915266
 
SASH1: a candidate tumor suppressor gene on chromosome 6q24.3 is downregulated in breast cancer.
Zeller C, Hinzmann B, Seitz S, Prokoph H, Burkhard-Goettges E, Fischer J, Jandrig B, Schwarz LE, Rosenthal A, Scherneck S.
Oncogene. 2003 May 15;22(19):2972-83.
PMID 12771949
 
SASH1 regulates melanocyte transepithelial migration through a novel Gαs-SASH1-IQGAP1-E-Cadherin dependent pathway.
Zhou D, Wei Z, Deng S, Wang T, Zai M, Wang H, Guo L, Zhang J, Zhong H, He L, Xing Q.
Cell Signal. 2013 Jun;25(6):1526-38. doi: 10.1016/j.cellsig.2012.12.025. Epub 2013 Jan 16.
PMID 23333244
 

Citation

This paper should be referenced as such :
Janssen, KP
SASH1 (SAM, SH3 domain containing 1)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(4):236-238.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/SASH1ID43799ch6q24.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Lung: Translocations in Squamous Cell Carcinoma


External links

Nomenclature
HGNC (Hugo)SASH1   19182
Cards
AtlasSASH1ID43799ch6q24
Entrez_Gene (NCBI)SASH1  23328  SAM and SH3 domain containing 1
AliasesSH3D6A; dJ323M4.1
GeneCards (Weizmann)SASH1
Ensembl hg19 (Hinxton)ENSG00000111961 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000111961 [Gene_View]  chr6:148272276-148552050 [Contig_View]  SASH1 [Vega]
ICGC DataPortalENSG00000111961
TCGA cBioPortalSASH1
AceView (NCBI)SASH1
Genatlas (Paris)SASH1
WikiGenes23328
SOURCE (Princeton)SASH1
Genetics Home Reference (NIH)SASH1
Genomic and cartography
GoldenPath hg38 (UCSC)SASH1  -     chr6:148272276-148552050 +  6q24.3-q25.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SASH1  -     6q24.3-q25.1   [Description]    (hg19-Feb_2009)
EnsemblSASH1 - 6q24.3-q25.1 [CytoView hg19]  SASH1 - 6q24.3-q25.1 [CytoView hg38]
Mapping of homologs : NCBISASH1 [Mapview hg19]  SASH1 [Mapview hg38]
OMIM607955   
Gene and transcription
Genbank (Entrez)AB018333 AI632133 AJ420508 AJ507735 AK023607
RefSeq transcript (Entrez)NM_001346505 NM_001346506 NM_001346507 NM_001346508 NM_001346509 NM_015278
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)SASH1
Cluster EST : UnigeneHs.193133 [ NCBI ]
CGAP (NCI)Hs.193133
Alternative Splicing GalleryENSG00000111961
Gene ExpressionSASH1 [ NCBI-GEO ]   SASH1 [ EBI - ARRAY_EXPRESS ]   SASH1 [ SEEK ]   SASH1 [ MEM ]
Gene Expression Viewer (FireBrowse)SASH1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)23328
GTEX Portal (Tissue expression)SASH1
Protein : pattern, domain, 3D structure
UniProt/SwissProtO94885   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO94885  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO94885
Splice isoforms : SwissVarO94885
PhosPhoSitePlusO94885
Domaine pattern : Prosite (Expaxy)SAM_DOMAIN (PS50105)   
Domains : Interpro (EBI)rSAM/SH3_domain-containing    SAM    SAM/pointed    SH3_2    SH3_domain   
Domain families : Pfam (Sanger)SAM_1 (PF00536)    SAM_2 (PF07647)    SH3_2 (PF07653)    SLY (PF12485)   
Domain families : Pfam (NCBI)pfam00536    pfam07647    pfam07653    pfam12485   
Domain families : Smart (EMBL)SAM (SM00454)  SH3 (SM00326)  
Conserved Domain (NCBI)SASH1
DMDM Disease mutations23328
Blocks (Seattle)SASH1
PDB (SRS)2DL0    2EBP   
PDB (PDBSum)2DL0    2EBP   
PDB (IMB)2DL0    2EBP   
PDB (RSDB)2DL0    2EBP   
Structural Biology KnowledgeBase2DL0    2EBP   
SCOP (Structural Classification of Proteins)2DL0    2EBP   
CATH (Classification of proteins structures)2DL0    2EBP   
SuperfamilyO94885
Human Protein AtlasENSG00000111961
Peptide AtlasO94885
HPRD06408
IPIIPI00304817   IPI01010180   IPI01011555   IPI00871313   IPI00478570   
Protein Interaction databases
DIP (DOE-UCLA)O94885
IntAct (EBI)O94885
FunCoupENSG00000111961
BioGRIDSASH1
STRING (EMBL)SASH1
ZODIACSASH1
Ontologies - Pathways
QuickGOO94885
Ontology : AmiGOprotein polyubiquitination  protein C-terminus binding  positive regulation of endothelial cell migration  protein kinase binding  mitogen-activated protein kinase kinase kinase binding  positive regulation of lipopolysaccharide-mediated signaling pathway  protein complex scaffold  protein complex  positive regulation of JUN kinase activity  positive regulation of angiogenesis  regulation of protein K63-linked ubiquitination  positive regulation of p38MAPK cascade  positive regulation of NIK/NF-kappaB signaling  regulation of protein autoubiquitination  
Ontology : EGO-EBIprotein polyubiquitination  protein C-terminus binding  positive regulation of endothelial cell migration  protein kinase binding  mitogen-activated protein kinase kinase kinase binding  positive regulation of lipopolysaccharide-mediated signaling pathway  protein complex scaffold  protein complex  positive regulation of JUN kinase activity  positive regulation of angiogenesis  regulation of protein K63-linked ubiquitination  positive regulation of p38MAPK cascade  positive regulation of NIK/NF-kappaB signaling  regulation of protein autoubiquitination  
NDEx NetworkSASH1
Atlas of Cancer Signalling NetworkSASH1
Wikipedia pathwaysSASH1
Orthology - Evolution
OrthoDB23328
GeneTree (enSembl)ENSG00000111961
Phylogenetic Trees/Animal Genes : TreeFamSASH1
HOVERGENO94885
HOGENOMO94885
Homologs : HomoloGeneSASH1
Homology/Alignments : Family Browser (UCSC)SASH1
Gene fusions - Rearrangements
Fusion : MitelmanMLLT4/SASH1 [6q27/6q24.3]  [t(6;6)(q24;q27)]  
Fusion : MitelmanSASH1/ARID1B [6q24.3/6q25.3]  [t(6;6)(q24;q25)]  
Fusion : MitelmanSASH1/DPF3 [6q24.3/14q24.2]  [t(6;14)(q24;q24)]  
Fusion : MitelmanSASH1/MLLT4 [6q24.3/6q27]  [t(6;6)(q24;q27)]  
Fusion: TCGAMLLT4 6q27 SASH1 6q24.3 LGG
Fusion: TCGASASH1 6q24.3 ARID1B 6q25.3 BRCA
Fusion: TCGASASH1 6q24.3 MLLT4 6q27 LGG
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSASH1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SASH1
dbVarSASH1
ClinVarSASH1
1000_GenomesSASH1 
Exome Variant ServerSASH1
ExAC (Exome Aggregation Consortium)SASH1 (select the gene name)
Genetic variants : HAPMAP23328
Genomic Variants (DGV)SASH1 [DGVbeta]
DECIPHERSASH1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSASH1 
Mutations
ICGC Data PortalSASH1 
TCGA Data PortalSASH1 
Broad Tumor PortalSASH1
OASIS PortalSASH1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSASH1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSASH1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch SASH1
DgiDB (Drug Gene Interaction Database)SASH1
DoCM (Curated mutations)SASH1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SASH1 (select a term)
intoGenSASH1
NCG5 (London)SASH1
Cancer3DSASH1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM607955   
Orphanet19148    23554   
MedgenSASH1
Genetic Testing Registry SASH1
NextProtO94885 [Medical]
TSGene23328
GENETestsSASH1
Target ValidationSASH1
Huge Navigator SASH1 [HugePedia]
snp3D : Map Gene to Disease23328
BioCentury BCIQSASH1
ClinGenSASH1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD23328
Chemical/Pharm GKB GenePA134984521
Clinical trialSASH1
Miscellaneous
canSAR (ICR)SASH1 (select the gene name)
Probes
Litterature
PubMed45 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSASH1
EVEXSASH1
GoPubMedSASH1
iHOPSASH1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Mon Sep 18 17:14:02 CEST 2017

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