Ectodomain Shedding and Regulated Intracellular Proteolysis in the Central Nervous System

Abstract

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 mediate it. 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 molecule's 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 known as Regulated Intracellular Proteolysis (RIP). This second proteolytic cleavage delivers molecule's intracellular domain (ICD) that carry 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.

Fractalkine shedding is mediated by p38 and the ADAM10 protease under pro-inflammatory conditions in human astrocytes

“…Transmembrane proteins, such as CX3CL1, can be proteolytically cleaved at the juxtamembrane region, which results in the detachment of their extracellular region (ectodomain) in a process known as ectodomain shedding [18]. This shedding process can release proteins such as cytokines and growth factors from their membrane-bound form, or alternatively, it can down-regulate receptors from the cell surface [18].…”

“…This shedding process can release proteins such as cytokines and growth factors from their membrane-bound form, or alternatively, it can down-regulate receptors from the cell surface [18]. Proteases such as the matrix metalloprotease (MMP) family shed several cell surface substrates [19, 20].…”

Distinct Intracellular Domain Substrate Modifications Selectively Regulate Ectodomain Cleavage of NRG1 or CD44

“…any transmembrane proteins on the cell surface are subject to proteolytic cleavage of their ectodomains, predominantly by metalloproteases (ectodomain shedding) (1)(2)(3). Ectodomain shedding regulates numerous important molecules involved in signal transfer between the extracellular space and the cell's interior and thus influences many cellular functions (1,3).…”

“…Ectodomain shedding regulates numerous important molecules involved in signal transfer between the extracellular space and the cell's interior and thus influences many cellular functions (1,3). This includes, for example, the biological availability of epidermal growth factor (EGF) receptor ligands such as neuregulin (NRG1) (4,5) and the modulation of complex cellular phenotypes required for contact inhibition of cells involving the hyaluronic acid receptor CD44 (4).…”

NMDA Receptors in Astroglia: Chronology, Controversies, and Contradictions from a Complex Molecule

“…Interestingly, it has been reported that NMDAR has been found to associate with metabotropic dopamine receptors [149]. There is also a possibility that Ca 2+ flux-independent metabotropic-like NMDAR function could be the result of proteolytic cleavage, as that already reported for NMDAR subunit GluN1 [150], that occurs to other membrane molecules [151]. In addition, GluN2C subunit-mediated IC signaling, found highly expressed in most transcriptome analysis of astrocytes, but that has been poorly studied, could be involved.…”