The term Ectodomain Shedding (ES) refers to extracellular domain proteolytic release from cell membrane molecules. This proteolysis is mediated mainly by matrix metalloproteases (MMP) or disintegrin and metalloproteases (ADAM), although some other proteases may participate. Virtually, all functional categories of cell membrane molecules are subject of this kind of proteolysis, for this reason ES is involved in different cellular processes such as proliferation, apoptosis, migration, differentiation or pathologies such as inflammation, cancer and degeneration among others. ES releases membrane molecules extracellular domain (or ectodomain) to the extracellular milieu where it can play different biological functions. ES of transmembrane molecules also generates membrane attached terminal fragments comprising transmembrane and intracellular domains that enable their additional processing by intracellular proteases, mechanism known as Regulated Intracellular Proteolysis (RIP). This second proteolytic cleavage delivers molecules intracellular domain (ICD) that carries out intracellular functions. RIP is mediated by the group of intracellular cleaving proteases (i- CLiPs) that include presenilin from the γ-secretase complex. In the CNS the best well known ES is that of the Amyloid Precursor Protein, although many other membrane molecules expressed by cells of the CNS are also subject to ES and RIP. In this review, these molecules are summarized, and some meaningful examples are highlighted and described. In addition, ES and RIP implications in the context of cell biology are discussed. Finally, some considerations that rise from the study of ES and RIP are formulated in view of the unexpected roles of intracellular fragments.
Keywords: Ectodomain shedding, regulated intracellular proteolysis, metalloprotease, ADAM, MMP, presenilin, γ-secretase, i- CLiPs, matrix metalloproteases (MMP), metalloproteases, ectodomain, Regulated Intracellular Proteolysis (RIP), Amyloid, ectodomain shedding (ES), glycophosphatidylinositol (GPI), Alzheimer Disease (AD), zymogens, carboxy-terminal (CTF), amino-terminal (NTF), presenilin (PS), 2 metalloproteases (S2P), aspartyl proteases (SPP), intracellular domains (ICD), microglia, oligodendroglia, Blood Brain Barrier, receptor ligands (RL), antigen presenting molecules (AP), Protein Tyrosine Phosphatase Family (RPTPF), G-protein Coupled Receptors (GPCR), Fractalkine, Neurofascin, Neuregulin, Vasorin, receptor tyrosine phosphatase family (RPTPF), ionomycin, immunofluorescence assay, Nerve Growth Factor (NGF), protein kinase C (PKC), γ chain (γc), proteosomal inhibition, juxtacrine cell communication, cytokines, ephrinB receptor (EphB), c-terminal Src kinase (Csk), Promyelocytic leukemia zinc finger protein (PLZF), FasL, cell adhesion molecules (CAM's), Heparan Sulfate Proteoglycan (HSPG), Calcium/calmodulin-dependent Serine Protein Kinase (CASK), γ-protocadherins (γ-pcdh), LFA-1, phosphorylation, palmitoylation, glycosilation, ubiquitination, α-secretase, β-secretase, nuclear localization sequence (NLS), lysosomal pathway, exosome pathway, Amyloid precursor protein, c-terminal SRC kinase, Mitogen activated protein kinase, Matrix metalloprotease, protocadherin, Promyelocytic leukemia zinc finger protein, Western blot
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