Ectodomain or Extracellular Doman


The extracellular domain of a transmembrane protein having specific function is referred to an ectodomain and is released by limited proteolysis in a processing referred to as ectodomain shedding (Arribas, J. and Borroto, A., Protein ectodomain shedding, Chem.Rev. 102, 4627-4638, 2002; Hartmann, M., Herrlich, A., and Herrlich, P., Who decides to cleave an ectodomain?, Trends Biochem.Sci. 38, 111-120, 2013; Tien, W.S., Chen, J.H., and Wu,  K.P., SheddomeDB: the ectodomain shedding database for membrane-bound shed markers, BMC Bioinformatics 18(Suppl 3): 42, 2017).  Ectodomain shedding is mediated by ADAM (a disintegrin and metallo) proteinases and matrix metalloproteinases (MMPs)(Higashiyama, S. and Nanba, D., ADAM-mediated ectodomain shedding of HB-EGF in receptor cross-talk, Biochim.Biophys. Acta 1751, 110-117, 2005; Clark, P., Protease-mediated ectodomain shedding, Thorax  69, 682-684, 2014).  There is particular interest in the role of ADAM10 (Wetzel, S.,Seipold, L., and Saftig, P., The metalloproteinase ADAM10: A useful therapeutic target?., Biochim.Biophys.Acta 1864, 2071-2081, 2017; Peron, R., Vatanabe, I.P., Mazine, P.R., Camins, A., and Cominetti, M.R., Pharmaceuticals(Basal) 11(1):12, 2018) and ADAM 17 which is also know as tumor necrosis factor-alpha-converting enzyme (Rego, S.L., Helms, R.S., and Dréau, D., Tumor necrosis factor-alpha-converting enzyme activities and tumor-associated macrophages in breast cancer, Immunol.Res. 58, 87-100, 2014).   Ectodomain shedding is involved in the genesis of Alzheimer’s disease (Zhang, H., Ma, Q., Zhang, Y.W., and Xu, H., Proteolytic processing of Alzheimer’s β-amyloid precursor protein, J.Neurochem. 120 (Suppl. 1), 9-21, 2012; Saftig, P. and Lichtenthaler, S.F., The alpha-secretase ADAM10: A metalloprotease with multiple functions in the brain, Prog.Neurobiol. 135, 1-20, 2015).   Ectodomain shedding is a critical factor in the function of cells such as the participation of neutrophils in inflammation (Garton, K.J., Gough, P.J., and Raines, E.W., Emerging roles for ectodomain shedding in the regulation of inflammatory responses, J.Leukoc.Biol. 79, 1105-1116, 2006; Mishra, H.K., Ma, J., and Walcheck, B., Ectodomain shedding by ADAM17: Its role in neutrophil recruitment and the impairment of the process during sepsis, Front.Cell Infect.Microbiol. 7:138, 2017).  The term extracellular domain apprears to be used to describe the portion of a transmembrane protein outside of the cell such as a receptor which may be released by proteolysis but as part of a process different from ectodomain shedding (Tsé, C., Gauchez, A.S. Jacot, W., and Lamy, P.J., HER2 shedding and serum HER2 extracellular domain: biology and clinical utility in breast cancer, Cancer Treat.Rev. 38, 133-142, 2012; Zarei, O., Benvenuti, S., Ustun-Alkan, F., Hamzeh-Mivehroud, M., and Dastmalchi, S., Strategies of targeting the extracellular domain of RON tyrosine kinase receptor for cancer therapy and drug delivery, J.Cancer Res.Clin.Oncol. 142, 2429-2446, 2016; Riquelme, M.A, Kar, R., Gu, S., and Jiang, J.S., Antibodies targeting extracellular domain of connexins for studies of hemichannels, Neuropharmacology 75, 525-532, 2013)