Molecular and cellular mechanisms of ectodomain shedding - PubMed (original) (raw)

Review

Molecular and cellular mechanisms of ectodomain shedding

Kazutaka Hayashida et al. Anat Rec (Hoboken). 2010 Jun.

Abstract

The extracellular domain of several membrane-anchored proteins is released from the cell surface as soluble proteins through a regulated proteolytic mechanism called ectodomain shedding. Cells use ectodomain shedding to actively regulate the expression and function of surface molecules, and modulate a wide variety of cellular and physiological processes. Ectodomain shedding rapidly converts membrane-associated proteins into soluble effectors and, at the same time, rapidly reduces the level of cell surface expression. For some proteins, ectodomain shedding is also a prerequisite for intramembrane proteolysis, which liberates the cytoplasmic domain of the affected molecule and associated signaling factors to regulate transcription. Ectodomain shedding is a process that is highly regulated by specific agonists, antagonists, and intracellular signaling pathways. Moreover, only about 2% of cell surface proteins are released from the surface by ectodomain shedding, indicating that cells selectively shed their protein ectodomains. This review will describe the molecular and cellular mechanisms of ectodomain shedding, and discuss its major functions in lung development and disease.

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Fig. 1

Fig. 1

Regulatory mechanisms of ectodomain shedding. Mechanisms as diverse as protein–protein interactions, phosphorylation, intracellular trafficking, polarized secretion, and activation of sheddases contribute to the regulation of ectodomain shedding at the cell surface. Several examples are shown. (1) Intracellular protein–protein interaction: Calmodulin constitutively bound to the cytoplasmic tail of substrates (e.g., L-selectin, ACE) inhibits ectodomain shedding, and the dissociation of calmodulin induced by calmodulin kinase enhances shedding. In contrast, PMA stimulation induces the association of moesin, potentiating the shedding of substrates (e.g., L-selectin). (2) Extracellular protein–protein interaction: Binding of ARTS-1 to cytokine receptors, such as TNFRI and IL-6R, activates shedding possibly by inducing a conformational change in the substrate or by displacing an inhibitory factor from the substrate. (3) Intracellular trafficking of substrate: BiP binds to substrates (e.g., ACE) and retains the substrate in the ER, preventing its encounter with the sheddase at the cell surface. (4) Phosphorylation of sheddase: PTKs or PKCs may activate the sheddase through Tyr or Ser/Thr phosphorylation of the cytoplasmic tail of the membrane-associated sheddase. (5) Activation of sheddase: Sheddases belonging to the ADAM or MMP family are activated by removal of the prodomain by furin and furin-like PCs in the trans Golgi compartment and also at the cell surface. (6) Intracellular trafficking of sheddase: TACE/ADAM17 is trafficked to the cell surface in a phosphorylation-dependent manner. For example, gastrin-releasing peptide activates a Src-PI3K-PDK pathway that induces Ser/Thr phosphorylation and promotes ADAM translocation to the cell surface. (7) Mobilization to specific membrane compartments: The substrate and sheddase can be secreted or sequestered in a polarized fashion to a specific membrane compartment on the cell surface or in intracellular compartments, which can accelerate the encounter of sheddase and substrate. (8) Interaction with modifying proteins on an adjacent cell: Binding of DSL ligand to heterodimeric Notch on an adjacent cell induces the endocytosis of the Notch-DSL ligand complex by DSL ligand expressing cells, providing a mechanical force to dissociate heterodimeric Notch and activate Notch shedding and signaling.

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