Degradomic-based approaches to elucidate (patho-)physiological functions of the metalloprotease meprin β

In this thesis, degradomic-based approaches - combining unbiased and targeted analyses in both in vitro and in vivo settings - were employed to investigate physiological and pathophysiological roles of the metalloprotease meprin β. Expressed in the kidney, skin, brain, and gut, meprin β participates in complex proteolytic networks, cleaving various soluble and transmembrane substrates. Therefore, dysregulation of meprin β is associated with different diseases, such as Alzheimer’s disease and cancer. 
Genomic studies of human cancer samples have identified numerous single-nucleotide variants (SNVs) within the gene coding for meprin β. Especially cancer-associated SNVs affecting the active site of proteases may largely impact their cleavage specificity, substrate processing, and, ultimately, cancer cell behavior. To facilitate systematic studies, a Targeted Approach to determine the impact of Cancer-Associated Protease variants (TACAP) was developed and applied to analyze the meprin β R238Q variant. This amino acid exchange at the S1’ position of meprin β leads to a loss of its characteristic cleavage preference for acidic amino acids at P1’ position, accompanied by changes in the substrate pool and inhibitor efficiencies compared to meprin β wildtype (wt). Functional in cellulo and ex vivo analyses provided evidence that the expression of meprin β and its cancer-associated variants promotes tumor cell invasiveness and migration. Furthermore, in cellulo and in vivo consequences of the proteolytic processing of transferrin receptor I (TfRI)  and latrophilin-3 were analyzed.   
In conclusion, this thesis demonstrates the power of degradomic-based analyses to uncover novel protease-substrate interactions and their functional relevance. 

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