The conserved WW-domain binding sites in Dystroglycan C-terminus are essential but partially redundant for Dystroglycan function.

BACKGROUND: Dystroglycan (Dg) is a transmembrane protein that is a part of the Dystrophin Glycoprotein Complex (DGC) which connects the extracellular matrix to the actin cytoskeleton. The C-terminal end of Dg contains a number of putative SH3, SH2 and WW domain binding sites. The most C-terminal PPXY motif has been established as a binding site for Dystrophin (Dys) WW-domain. However, our previous studies indicate that both Dystroglycan PPXY motives, WWbsI and WWbsII can bind Dystrophin protein in vitro. RESULTS: We now find that both WW binding sites are important for maintaining full Dg function in the establishment of oocyte polarity in Drosophila. If either WW binding site is mutated, the Dg protein can still be active. However, simultaneous mutations in both WW binding sites abolish the Dg activities in both overexpression and loss-of-function oocyte polarity assays in vivo. Additionally, sequence comparisons of WW binding sites in 12 species of Drosophila, as well as in humans, reveal a high level of conservation. This preservation throughout evolution supports the idea that both WW binding sites are functionally required. CONCLUSION: Based on the obtained results we propose that the presence of the two WW binding sites in Dystroglycan secures the essential interaction between Dg and Dys and might further provide additional regulation for the cytoskeletal interactions of this complex.

Evaluation of carcinogenic risk in friction product workers.

Mortality rates of two cohorts of asbestos friction product (FP) workers were studied in comparison with the population of the adjoining towns over periods of 20 and 40 years respectively. The second cohort was subdivided into 3 subcohorts exposed to chrysotile asbestos (CA), vulcanization and/or polymerization vapours and gases (VPGV) and asbestos bakelite (AB) or asbestos rubber (AR) dusts. In the first cohort no deaths from lung cancer were recorded, even though the total tumour mortality was higher than in the general population. In the second cohort an excess tumour mortality was observed in the first subcohort for stomach cancer only. In the other two subcohorts the expected rates were higher for all the tumour sites. Following intraperitoneal injection of CA, AB and AR dusts, malignant tumours developed in 31.5% of the rats which received CA, and in about 10% of the rats which were injected with AB and AR dusts. Also, the mean longevity of CA-treated animals was significantly lower than in the other two groups. Thus, the carcinogenic risk was real in the group of FP production workers with significant CA exposure only.