Targeted approach to determine the impact of cancer-associated protease variants.

Several steps of cancer progression, from tumor onset to metastasis, critically involve proteolytic activity. To elucidate the role of proteases in cancer, it is particularly important to consider single-nucleotide variants (SNVs) that affect the active site of proteases, thereby influencing cleavage specificity, substrate processing, and thus cancer cell behavior. To facilitate systematic studies, we here present a targeted approach to determine the impact of cancer-associated protease variants (TACAP).

Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases.

Proteolytic cell surface release ('shedding') of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, for the human body neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated thus far.

A novel mouse model for N-terminal truncated Aβ2-x generation through meprin β overexpression in astrocytes.

Neurotoxic amyloid-β (Aβ) peptides cause neurodegeneration in Alzheimer's disease (AD) patients' brains. They are released upon proteolytic processing of the amyloid precursor protein (APP) extracellularly at the β-secretase site and intramembranously at the γ-secretase site. Several AD mouse models were developed to conduct respective research in vivo.

Identification of PCPE-2 as the endogenous specific inhibitor of human BMP-1/tolloid-like proteinases.

BMP-1/tolloid-like proteinases (BTPs) are major players in tissue morphogenesis, growth and repair. They act by promoting the deposition of structural extracellular matrix proteins and by controlling the activity of matricellular proteins and TGF-β superfamily growth factors. They have also been implicated in several pathological conditions such as fibrosis, cancer, metabolic disorders and bone diseases.

Proteolytic processing of galectin-3 by meprin metalloproteases is crucial for host-microbiome homeostasis.

The metalloproteases meprin α and meprin β are highly expressed in the healthy gut but significantly decreased in inflammatory bowel disease, implicating a protective role in mucosal homeostasis. In the colon, meprin α and meprin β form covalently linked heterodimers tethering meprin α to the plasma membrane, therefore presenting dual proteolytic activity in a unique enzyme complex. To unravel its function, we applied N-terminomics and identified galectin-3 as the major intestinal substrate for meprin α/β heterodimers.