SASH1 (SAM and SH3 domain containing 1)

2013-08-01 Klaus-Peter Janssen Affiliation

Department of Surgery, Technische Universitaet Muenchen, Ismaninger Str 22, 81675 Munich, Germany

Identity

HGNC

SASH1

LOCATION

6q24.3

LOCUSID

23328

ALIAS

CAPOK,DUH1,SH3D6A,dJ323M4.1

FUSION GENES

Show Gene Fusions

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.

Proteins

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

Entity name

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 name

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 name

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 name

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 name

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

Pubmed ID	Last Year	Title	Authors
22488244	2012	Effects of SASH1 on lung cancer cell proliferation, apoptosis, and invasion in vitro.	Chen EG et al
23023727	2012	Effects of SASH1 on melanoma cell proliferation and apoptosis in vitro.	Lin S et al
21820526	2011	The candidate tumor suppressor SASH1 interacts with the actin cytoskeleton and stimulates cell-matrix adhesion.	Martini M et al
23108792	2013	SASH1 regulates proliferation, apoptosis, and invasion of osteosarcoma cell.	Meng Q et al
23095620	2012	Integrative marker analysis allows risk assessment for metastasis in stage II colon cancer.	Nitsche U et al
17088907	2006	Prognostic significance of downregulated expression of the candidate tumour suppressor gene SASH1 in colon cancer.	Rimkus C et al
22915266	2012	Overexpression of SASH1 related to the decreased invasion ability of human glioma U251 cells.	Yang L et al
12771949	2003	SASH1: a candidate tumor suppressor gene on chromosome 6q24.3 is downregulated in breast cancer.	Zeller C et al
23333244	2013	SASH1 regulates melanocyte transepithelial migration through a novel Gαs-SASH1-IQGAP1-E-Cadherin dependent pathway.	Zhou D et al

Other Information

Locus ID:

NCBI: 23328
MIM: 607955
HGNC: 19182
Ensembl: ENSG00000111961

Variants:

dbSNP: 23328
ClinVar: 23328
TCGA: ENSG00000111961
COSMIC: SASH1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000111961	ENST00000367467	O94885
ENSG00000111961	ENST00000622663	A0A087WW74
ENSG00000111961	ENST00000636279	A0A1B0GWB9
ENSG00000111961	ENST00000637469	A0A1B0GVF9
ENSG00000111961	ENST00000637729	A0A1B0GVI0

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
19913121	2009	Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.	85
20379614	2010	Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.	62
12771949	2003	SASH1: a candidate tumor suppressor gene on chromosome 6q24.3 is downregulated in breast cancer.	47
17088907	2006	Prognostic significance of downregulated expression of the candidate tumour suppressor gene SASH1 in colon cancer.	32
18978678	2008	Candidate gene/loci studies in cleft lip/palate and dental anomalies finds novel susceptibility genes for clefts.	21
23108792	2013	SASH1 regulates proliferation, apoptosis, and invasion of osteosarcoma cell.	17
21820526	2011	The candidate tumor suppressor SASH1 interacts with the actin cytoskeleton and stimulates cell-matrix adhesion.	16
22915266	2012	Overexpression of SASH1 related to the decreased invasion ability of human glioma U251 cells.	15
26350878	2016	Genome-wide association study for rotator cuff tears identifies two significant single-nucleotide polymorphisms.	13
27178818	2016	Overexpression of SASH1 Inhibits TGF-β1-Induced EMT in Gastric Cancer Cells.	13

Citation

Klaus-Peter Janssen

SASH1 (SAM and SH3 domain containing 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-08-01

Online version: http://atlasgeneticsoncology.org/gene/43799/sash1