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Nodal is a secreted protein of the transforming growth factor beta (TGFbeta) family that activates Smad2 and Smad3 transcription factors through complexes of type I and type II activin receptors and glycosyl-phosphatidylinositol-anchored coreceptors of the epidermal growth factor-like Cripto/FRL-1/Cryptic family. During early embryogenesis, it stimulates the proliferation of pluripotent progenitor cells and specifies, in a dosage-dependent manner, their subsequent allocation to distinct germ layers. Available evidence indicates that the signaling strength of Nodal is controlled at the level of endocytic uptake and turnover of activated receptor complexes in early endosomes, but insights into the underlying molecular mechanisms are still limited. In this review, I briefly survey literature on the trafficking of the related TGFbeta receptors, and I discuss recent findings indicating that endocytosis of Nodal is coupled to proteolytic processing of its precursor at the cell surface and that the maturation and internalization of Nodal need to be guided by Cripto to stabilize endosomal signaling platforms.

Background— Genetic studies demonstrated the presence of risk alleles in the genes ANRIL and CAMTA1/VAMP3 that are shared between coronary artery disease (CAD) and periodontitis. We aimed to identify further shared genetic risk factors to better understand conjoint disease mechanisms. Methods and Results— In-depth genotyping of 46 published CAD risk loci of genome-wide significance in the worldwide largest case–control sample of the severe early-onset phenotype aggressive periodontitis (AgP) with the Illumina Immunochip (600 German AgP cases, 1448 controls) and the Affymetrix 500K array set (283 German AgP cases and 972 controls) highlighted ANRIL as the major risk gene and revealed further associations with AgP for the gene PLASMINOGEN ( PLG ; rs4252120: P =5.9×10 −5 ; odds ratio, 1.27; 95% confidence interval, 1.3–1.4 [adjusted for smoking and sex]; 818 cases; 5309 controls). Subsequent combined analyses of several genome-wide data sets of CAD and AgP suggested TGFBRAP1 to be associated with AgP (rs2679895: P =0.0016; odds ratio, 1.27 [95% confidence interval, 1.1–1.5]; 703 cases; 2.143 controls) and CAD ( P =0.0003; odds ratio, 0.84 [95% confidence interval, 0.8–0.9]; n=4117 cases; 5824 controls). The study further provides evidence that in addition to PLG , the currently known shared susceptibility loci of CAD and periodontitis, ANRIL and CAMTA1/VAMP3 , are subjected to transforming growth factor-β regulation. Conclusions— PLG is the third replicated shared genetic risk factor of atherosclerosis and periodontitis. All known shared risk genes of CAD and periodontitis are members of transforming growth factor-β signaling.