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Protein ectodomain shedding and its functional consequences

    

 

 

The most well-known function of catalytically active ADAMs, such as ADAM-17, is to cleave ectodomains of various transmembrane proteins. The proteolysis usually occurs at the membrane-adjacent part of the molecule. Proteins with different function can be processed by ectodomain shedding.


ELISA(enzyme-linked immunosorbent assay) is a method for detecting the concentration of some kind antigen or antibody,such as ADAMs, using the characteristic of specific binding between antigen-antibody. Meretciel provide high quality ELISA kits for R&D,can syudy the role of ADAMs.


Protein cleavage can regulate cellular signaling and affect cell behavior, but the result always depends on the cellular context. Because both substrate and receptor can be cleaved, several scenarios are possible. The cleaved substrate can bind to its receptor and then the activated receptor initiates downstream signaling events.For example, ADAM-17 can cleave HB-EGF which, in turn, activates EGFR and initiates cell proliferation . However, the receptor can be cleaved from the cell surface; thus, ectodomain shedding can actually stop the ligand-initiated signaling: ADAM-17-induced macrophage colony-stimulating factor receptor cleavage downregulates activated macrophages . 


Failure in receptor downregulation and normal turnover can have serious consequences as observed in TNF-receptor associated periodic febrile syndrome (TRAPS). A mutation in the cleavage site of the TNF receptor I can lead to receptor accumulation on the cell surface due to inefficient shedding. Receptor abundance increases cell susceptibility to TNF-α and TRAPS patients have increased inflammatory responses with concomitant fever . If the receptor shedding occurs before the ligand binding, the receptor can serve as a decoy and inhibit the ligand binding to cell surface receptors.


Interestingly, activation of membrane-bound receptors by ligand binding can result in either cell proliferation or apoptosis depending on which other signaling pathways are activated or “connected” to the host-receptors pathway. Therefore, inhibiting or knocking down a receptor which activates inhibitory signaling pathways can actually activate the previously inhibited processes. An example of this mechanism is the contribution of EGFR activation to normal heart development through the Smad/BMP signaling pathway. EGFR activates Smad signaling, thereby inhibiting hyperproliferation of cells in developing heart valves. Furthermore, Smad6−/− mice were confirmed to have enlarged heart valves and that EGFR knockout mice and HB-EGF−/− mice develop hyperplasic heart valves, too. Insufficient or inactive EGFR during heart valve development therefore hinders activation of an inhibitory mechanism (Smad) and leads to activation of a proliferative pathway.

 

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