Regulation of ADAM10 by the TspanC8 Family of Tetraspanins and Their Therapeutic Potential

• Published in: International journal of molecular sciences Vol. 22; no. 13; p. 6707
• Main Authors: Harrison, Neale, Koo, Chek Ziu, Tomlinson, Michael G
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23.06.2021; MDPI
• Subjects: ADAM10; ADAM10 Protein - physiology; Alzheimer's disease; Amino acid sequence; Amyloid precursor protein; Amyloid Precursor Protein Secretases - physiology; Animals; Antibodies; Asthma; Breast cancer; Cadherins - metabolism; Cancer therapies; Cell surface; Clinical trials; Clustering; ectodomain shedding; Enzymes; Epidermal growth factor; Growth factors; Humans; Immunoglobulins; Ligands; membrane protein; Membrane proteins; Membrane Proteins - metabolism; Membrane Proteins - physiology; Membranes; metalloproteinase; Molecular Targeted Therapy - methods; Morphogenesis; Proteins; Regulation; Review; Secretase; Subgroups; Substrates; tetraspanin; Tetraspanins - chemistry; Tetraspanins - physiology; TspanC8; ADAM10; membrane protein; TspanC8; ectodomain shedding; tetraspanin; metalloproteinase
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22136707

The ubiquitously expressed transmembrane protein a disintegrin and metalloproteinase 10 (ADAM10) functions as a "molecular scissor", by cleaving the extracellular regions from its membrane protein substrates in a process termed ectodomain shedding. ADAM10 is known to have over 100 substrates including Notch, amyloid precursor protein, cadherins, and growth factors, and is important in health and implicated in diseases such as cancer and Alzheimer's. The tetraspanins are a superfamily of membrane proteins that interact with specific partner proteins to regulate their intracellular trafficking, lateral mobility, and clustering at the cell surface. We and others have shown that ADAM10 interacts with a subgroup of six tetraspanins, termed the TspanC8 subgroup, which are closely related by protein sequence and comprise Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33. Recent evidence suggests that different TspanC8/ADAM10 complexes have distinct substrates and that ADAM10 should not be regarded as a single scissor, but as six different TspanC8/ADAM10 scissor complexes. This review discusses the published evidence for this "six scissor" hypothesis and the therapeutic potential this offers.