| Note |
Entrez Gene: 23328 C, Ensembl: ENSG00000111961 C, UCSC: uc003qme.1 D, Vega:OTTHUMG00000015773. |
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| | 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. |
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| 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. |
| 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). |
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| | 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). |
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| 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. |
| Note | |
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| 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). |
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| 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). |
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| 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). |
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| 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). |
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| 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).
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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