8.A.77 The Sheddase or ADAM (Sheddase) Family
Ectodomain shedding of integral membrane receptors, channels and transporters results in the release of soluble molecules and
modification of the transmembrane portions of the substrate proteins to mediate or modulate extracellular and intracellular
signalling. Ectodomain shedding is stimulated by a variety of mechanisms, including the activation
of P2 receptors by extracellular nucleotides. Metalloproteinases play the primary role in the shedding of various cell surface molecules
including amyloid precursor protein, CD23, CD62L, and members of the epidermal growth factor,
immunoglobulin and tumour necrosis factor families. Pupovac and Sluyter 2016 discuss the mechanisms involved in
shedding, demonstrating central roles for the P2 receptors, P2X7 (TC# 1.A.7.1.3) and P2Y2 (TC# 9.A.14.13.16), and
the sheddases, ADAM10 and ADAM17, in this process.
'A disintegrin and metalloproteases' (ADAMs) family serves diverse functions in multicellular organisms. About half of the ADAMs are active metalloproteases and cleave cell surface proteins, including growth factors, receptors, cytokines and cell adhesion proteins. Other ADAMs have no catalytic activity and function as adhesion proteins or receptors. Some ADAMs are ubiquitously expressed, while others are expressed tissue specifically. In the mammalian nervous system, non-proteolytic ADAM11, ADAM22 and ADAM23 have key functions in neural development, myelination and synaptic transmission and are linked to epilepsy. Among the proteolytic ADAMs, ADAM10 is the best characterized one due to its substrates Notch and amyloid precursor protein, where cleavage is required for nervous system development or linked to Alzheimer's disease (AD), respectively. ADAM10 has additional substrates, and its substrate selectivity may be regulated by tetraspanins. ADAM8 and ADAM17 are involved in neuroinflammation, while ADAM17 additionally regulates neurite outgrowth and myelination, and its activity is controlled by iRhoms. ADAM19 and ADAM21 function in regenerative processes upon neuronal injury. Several ADAMs, including ADAM9, ADAM10, ADAM15 and ADAM30, are potential drug targets for AD (Hsia et al. 2019).
ADAM10 is ubiquitously expressed and essential for embryonic development through activation of Notch proteins (Saftig and Lichtenthaler 2015). ADAM10 regulates over 40 other transmembrane proteins and acts as a 'molecular scissor' by removing their extracellular regions (Matthews et al. 2017). It is also a receptor for alpha-toxin, a major virulence factor of Staphylococcus aureus (Shah et al. 2018). Levels of the transmembrane ADAM9 and ADAM18 at the cell surface are regulated by sorting nexin9 (SNX9) (Mygind et al. 2018).
The ADAM11 protein (8.A.77.2.1) is an auxilary protein responsible for the localization of Kv1.1 and Kv1.2 K+ channel subunit complexes to the distal terminai of certain nerve cells (Kole et al. 2015). Direct interaction with Kv1 channel proteins has been demonstrated.