Regulation of membrane proteins and receptors by tetraspanins

I investigate how membrane proteins and receptors on human cells are regulated by a family of 33 tetraspanin ‘membrane organiser’ proteins.  A major focus is the regulation of the ‘molecular scissor’ ADAM10 by six tetraspanins that I have termed the TspanC8s.  These comprise Tspan5, 10, 14, 15, 17 and 33.  ADAM10 is essential for embryonic development and is expressed on all cells.  ADAM10 is critical for cellular development, activation and adhesion; it functions by proteolytically cleaving the extracellular regions from its target proteins that include the cell fate regulator Notch, amyloid precursor protein, cadherin adhesion molecules and the platelet-activating collagen/fibrin receptor GPVI.  We have proposed the “six scissor” hypothesis, whereby the associated TspanC8 dictates the subcellular localisation and substrate specificity of the ADAM10 scissor.  This has potential for therapeutic targeting of ADAM10 in a cell type- or substrate-specific manner, so minimising toxic side effects.  Diseases of interest include inflammatory diseases, heart attack and stroke, cancer, asthma and Alzheimer’s disease.