ADAM10 and Associated Diseases
Creative Biolabs is committed to accelerating the development of gene therapy. Based on our understanding of gene therapy and potential target genes, we now describe the ADAM10 gene and associated diseases for our clients all over the world.
Overview of ADAM10
Disintegrin and metalloproteinases (ADAMs) are single membrane-spanning proteases that exist in almost all tissues. Composed of an EGF-like domain, a cysteine-rich domain, a disintegrin domain, and a metalloproteinase domain, their transmembrane domains link the cytoplasmic C-terminal tail to the extracellular domain. As one of the most studied members of the ADAM family, the expression of ADAM10 can be detected in several tissues of mammals.
Fig.1 The role of ADAM10 in different human diseases. (Wetzel, 2017)
Functions of ADAM10
ADAM10 is responsible for the shedding of transmembrane proteins at the plasma membrane or in secretory vesicles. This process is a prerequisite for the ensuing regulated intramembrane proteolysis. The activity of ADAM10 can be regulated by a variety of mechanisms, including transcriptional and translational control, Furin and preprotein convertase 7 (PC7) control, as well as interaction with other proteins. For example, the binding of SAP97 or clathrin adaptor protein-2 (AP2) to the cytoplasmic portion of ADAM10 regulates its transport to the plasma membrane and internalization, respectively.
Fig.2 Drugs potentially modulating ADAM10 activity. (Wetzel, 2017)
ADAM10 Associated Diseases
Studies have shown that dysregulation of ADAM10 activity is associated with diverse human diseases. Amyloid precursor protein (APP) is an important protein involved in the pathogenesis of Alzheimer's disease (AD) and is one of the substrates of brain-specific ADAM10. ADAM10 has been identified as a key protease involved in a non-amyloidogenic pathway. In this case, up-regulated ADAM10 reduces proteolytic amyloid β (Aβ) production while favoring neuroprotective sAPPα production. In prion disease, ADAM10 mediates extracellular domain shedding of cellular prion protein (PrPc). Inhibition of ADAM10 expression results in a significant reduction in soluble PrPc levels, ultimately reducing the spread of prion-induced pathology. What’s more, ADAM10 is associated with a variety of cancers, including T-cell acute lymphoblastic leukemia (T-ALL) cancer, glioblastoma, breast cancer, and squamous cell carcinoma. In immune disorders, cytokines and chemokines play important roles in the immune system as substrates for the ADAM10 adhesion molecule. Therefore, ADAM10 is a potential therapeutic target for modulating immune diseases.
In conclusion, ADAM10 plays a central role in a variety of diseases, and selective enhancement or blockade of ADAM10 activity will provide important therapeutic values.
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Reference
- Wetzel, S.; et al. The metalloproteinase ADAM10: A useful therapeutic target? Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2017, 1864(11): 2071-2081.
