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

Neale Harrison,Michael G Tomlinson,Chek Ziu Koo

doi:10.3390/ijms22136707

Neale Harrison, Michael G Tomlinson + Show 1 more

Open Access

https://doi.org/10.3390/ijms22136707

Copy DOI

Abstract

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.

Highlights

The evolutionary conserved superfamily of Zn2+ dependent a disintegrin and metalloproteinases (ADAMs) are single pass transmembrane metalloproteinases that are responsible for the ectodomain shedding of a large number of transmembrane proteins
ADAMs share a common structure, comprising an N-terminal signal sequence followed by an inhibitory prodomain, a metalloproteinase domain, disintegrin domain, cysteine-rich region, an epidermal growth factor (EGF) domain, a transmembrane region, and a cytoplasmic tail
This review focuses on the regulation of a disintegrin and metalloproteinase 10 (ADAM10) by tetraspanins

Summary

Introduction

The evolutionary conserved superfamily of Zn2+ dependent a disintegrin and metalloproteinases (ADAMs) are single pass transmembrane metalloproteinases that are responsible for the ectodomain shedding of a large number of transmembrane proteins. This “molecular scissor” action can have dramatic effects on cell function, including the initiation of intracellular signaling pathways, downregulation of receptor signaling or adhesive function, or the release of soluble mediators such as growth factors, cytokines, or chemokines [1]. ADAM10 and ADAM17 are the best studied, largely due to knockout mouse studies that have highlighted their important roles in embryonic development and response to injury/infection, respectively. This review focuses on the regulation of ADAM10 by tetraspanins

Importance of the Molecular Scissor ADAM10 in Health and Disease

Tetraspanins Interact with and Regulate Other Membrane Proteins

Insights from Recent Tetraspanin Structural Studies

Findings

Concluding Remarks