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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.

References associated with 8.A.77 family:

Boskovski, M.T., S. Yuan, N.B. Pedersen, C.K. Goth, S. Makova, H. Clausen, M. Brueckner, and M.K. Khokha. (2013). The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality. Nature 504: 456-459. 24226769
Caolo, V., M. Debant, N. Endesh, T.S. Futers, L. Lichtenstein, F. Bartoli, G. Parsonage, E.A. Jones, and D.J. Beech. (2020). Shear stress activates ADAM10 sheddase to regulate Notch1 via the Piezo1 force sensor in endothelial cells. Elife 9:. 32484440
Guo, S., M. Peng, Q. Zhao, and W. Zhang. (2012). Role of ADAM10 and ADAM17 in CD16b shedding mediated by different stimulators. Chin Med Sci J 27: 73-79. 22770404
Hsia, H.E., J. Tüshaus, T. Brummer, Y. Zheng, S.D. Scilabra, and S.F. Lichtenthaler. (2019). Functions of ''A disintegrin and metalloproteases (ADAMs)'' in the mammalian nervous system. Cell Mol Life Sci 76: 3055-3081. 31236626
Jowett, J.B., Y. Okada, P.J. Leedman, J.E. Curran, M.P. Johnson, E.K. Moses, H.H. Goring, S. Mochizuki, J. Blangero, L. Stone, H. Allen, C. Mitchell, and V.B. Matthews. (2012). ADAM28 is elevated in humans with the metabolic syndrome and is a novel sheddase of human tumour necrosis factor-α. Immunol Cell Biol 90: 966-973. 23010875
Kole, M.J., J. Qian, M.P. Waase, T.L. Klassen, T.T. Chen, G.J. Augustine, and J.L. Noebels. (2015). Selective Loss of Presynaptic Potassium Channel Clusters at the Cerebellar Basket Cell Terminal Pinceau in Adam11 Mutants Reveals Their Role in Ephaptic Control of Purkinje Cell Firing. J. Neurosci. 35: 11433-11444. 26269648
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Mathews, J.A., D.R. Gibb, B.H. Chen, P. Scherle, and D.H. Conrad. (2010). CD23 Sheddase A disintegrin and metalloproteinase 10 (ADAM10) is also required for CD23 sorting into B cell-derived exosomes. J. Biol. Chem. 285: 37531-37541. 20876574
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Mishra, H.K., J. Ma, D. Mendez, R. Hullsiek, N. Pore, and B. Walcheck. (2020). Blocking ADAM17 Function with a Monoclonal Antibody Improves Sepsis Survival in a Murine Model of Polymicrobial Sepsis. Int J Mol Sci 21:. 32932701
Mygind, K.J., T. Störiko, M.L. Freiberg, J. Samsøe-Petersen, J. Schwarz, O.M. Andersen, and M. Kveiborg. (2018). Sorting nexin 9 (SNX9) regulates levels of the transmembrane ADAM9 at the cell surface. J. Biol. Chem. 293: 8077-8088. 29622675
Osanai, T., M. Tanaka, K. Mikami, M. Kitajima, T. Tomisawa, K. Magota, H. Tomita, and K. Okumura. (2018). Novel anti-aging gene NM_026333 contributes to proton-induced aging via NCX1-pathway. J Mol. Cell Cardiol 125: 174-184. 30385152
Prox, J., M. Willenbrock, S. Weber, T. Lehmann, D. Schmidt-Arras, R. Schwanbeck, P. Saftig, and M. Schwake. (2012). Tetraspanin15 regulates cellular trafficking and activity of the ectodomain sheddase ADAM10. Cell Mol Life Sci 69: 2919-2932. 22446748
Pupovac, A. and R. Sluyter. (2016). Roles of extracellular nucleotides and P2 receptors in ectodomain shedding. Cell Mol Life Sci. [Epub: Ahead of Print] 27180276
Saftig, P. and S.F. Lichtenthaler. (2015). The alpha secretase ADAM10: A metalloprotease with multiple functions in the brain. Prog Neurobiol 135: 1-20. 26522965
Shah, J., F. Rouaud, D. Guerrera, E. Vasileva, L.M. Popov, W.L. Kelley, E. Rubinstein, J.E. Carette, M.R. Amieva, and S. Citi. (2018). A Dock-and-Lock Mechanism Clusters ADAM10 at Cell-Cell Junctions to Promote α-Toxin Cytotoxicity. Cell Rep 25: 2132-2147.e7. 30463011
Thathiah, A., C.P. Blobel, and D.D. Carson. (2003). Tumor necrosis factor-alpha converting enzyme/ADAM 17 mediates MUC1 shedding. J. Biol. Chem. 278: 3386-3394. 12441351
Vázquez, F., G. Hastings, M.A. Ortega, T.F. Lane, S. Oikemus, M. Lombardo, and M.L. Iruela-Arispe. (1999). METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity. J. Biol. Chem. 274: 23349-23357. 10438512
Virreira Winter, S., A. Zychlinsky, and B.W. Bardoel. (2016). Genome-wide CRISPR screen reveals novel host factors required for Staphylococcus aureus α-hemolysin-mediated toxicity. Sci Rep 6: 24242. 27066838
von Hoven, G., A.J. Rivas, C. Neukirch, S. Klein, C. Hamm, Q. Qin, M. Meyenburg, S. Füser, P. Saftig, N. Hellmann, R. Postina, and M. Husmann. (2016). Dissecting the role of ADAM10 as a mediator of Staphylococcus aureus α-toxin action. Biochem. J. 473: 1929-1940. 27147619
Wewer, U.M., M. Mörgelin, P. Holck, J. Jacobsen, M.C. Lydolph, A.H. Johnsen, M. Kveiborg, and R. Albrechtsen. (2006). ADAM12 is a four-leafed clover: the excised prodomain remains bound to the mature enzyme. J. Biol. Chem. 281: 9418-9422. 16455653