Intracellular adaptor proteins are indispensable for the transduction of receptor-derived signals, as they recruit and connect essential downstream effectors. The SLy/SASH1-adaptor family comprises three highly homologous proteins, all of them sharing conserved structural motifs. The initial characterization of the first member SLy1/SASH3 (SH3 protein expressed in lymphocytes 1) in 2001 was rapidly followed by identification of SLy2/HACS1 (hematopoietic adaptor containing SH3 and SAM domains 1) and SASH1/SLy3 (SAM and SH3 domain containing 1). Based on their pronounced sequence similarity, they were subsequently classified as one family of intracellular scaffold proteins. Despite their obvious homology, the three SLy/SASH1-members fundamentally differ with regard to their expression and function in intracellular signaling. On the contrary, growing evidence clearly demonstrates an important role of all three proteins in human health and disease. In this review, we systematically summarize what is known about the SLy/SASH1-adaptors in the field of molecular cell biology and immunology. To this end, we recapitulate current research about SLy1/SASH3, SLy2/HACS1, and SASH1/SLy3, with an emphasis on their similarities and differences.

Cancers of the large intestine are among the most frequent malignomas worldwide and also rank among the most frequent causes for cancer-related mortality in developed countries, with an even increasing incidence in an aging population. Patient survival and treatment options in the metastatic form of this disease are still relatively poor. The cell-autonomous genetic and epigenetic changes associated with carcinogenesis, and the step-wise and consecutive progression along the adenoma-carcinoma sequence in the colorectum, have been studied intensively over the last decades. However, there is a growing interest in the impact of gut microbial communities on the initiation and progression of this cancer entity. Overwhelming evidence meanwhile suggests that the microbiota is an important and potentially causative factor for colorectal cancer (CRC). A disturbance in the microbial community may lead to impairment of epithelial barrier function, imbalance in epithelial self-renewal, DNA damage, and altered immune responses, thereby fostering tumor initiation and progression.

BackgroundEven though the post-operative outcome varies greatly among patients with nodal positive colon cancer (UICC stage III), personalized prediction of systemic disease recurrence is currently insufficient. We investigated in a retrospective setting whether genetic and immunological biomarkers can be applied for stratification of distant metastasis occurrence risk.MethodsEighty four patients with complete resection (R0) of stage III colon cancer from two clinical centres were analysed for genetic biomarkers: microsatellite instability, oncogenic mutations in KRAS exon2 and BRAF exon15, expression of osteopontin and the metastasis-associated genes SASH1 and MACC1. Tumor-infiltrating CD3 and CD8 positive T-cells were quantified by immunocytochemistry. Results were correlated with outcome and response to 5-FU based adjuvant chemotherapy, using Cox's proportional hazard models and integrative two-step cluster analysis.ResultsDistant metastasis risk was significantly correlated with oncogenic KRAS mutations (p=0.015), expression of SASH1 (p=0.016), and the density of CD8-positive T-cells (p=0.007) in Kaplan-Meier analysis. Upon multivariate Cox-regression analysis, KRAS mutation (p=0.008) and density of CD8-positive TILs (p=0.009) were retained as prognostic parameters for metachronous distant metastasis. Integrative two-step cluster analysis was used to combine all genetic markers, allowing stratification of patient subgroups. Post-operative distant metastasis risk ranged from 31% (low-risk) to 41% (intermediate), and 57% (high-risk) (p=0.032). Increased expression of osteopontin (p=0.019) and low density of CD8-positive T-cells (p=0.043) were significantly associated with unfavourable response to 5-FU.ConclusionsIntegrative biomarker analysis allows stratification of stage III colon cancer patients for the risk of metastatic disease recurrence and may indicate response to 5-FU. Thus, biomarker analysis might facilitate the use of adjuvant therapy for high risk patients.