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ADAM10 mediates shedding of carbonic anhydrase IX ectodomain non‑redundantly to ADAM17

Carbonic anhydrase IX (CA IX) is a transmembrane enzyme participating in adaptive responses of tumors to hypoxia and acidosis. CA IX regulates pH, facilitates metabolic reprogramming, and supports migration, invasion and metastasis of cancer cells. Extracellular domain (ECD) of CA IX can be shed to medium and body fluids by a disintegrin and metalloproteinase (ADAM) 17. Here we show for the first time that CA IX ECD shedding can be also executed by ADAM10, a close relative of ADAM17, via an overlapping cleavage site in the stalk region of CA IX connecting its exofacial catalytic site with the transmembrane region. This finding is supported by biochemical evidence using recombinant human ADAM10 protein, colocalization of ADAM10 with CA IX, ectopic expression of a dominant‑negative mutant of ADAM10 and RNA interference‑mediated suppression of ADAM10. Induction of the CA IX ECD cleavage with ADAM17 and/or ADAM10 activators revealed their additive effect. Similarly, additive effect was observed with an ADAM17‑inhibiting antibody and an ADAM10‑preferential inhibitor GI254023X. These data indicated that ADAM10 is a CA IX sheddase acting on CA IX non‑redundantly to ADAM17.

 

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The passage describes a study that investigated the shedding of the extracellular domain (ECD) of the transmembrane enzyme called Carbonic Anhydrase IX (CA IX). CA IX is involved in adaptive responses of tumors to hypoxia (low oxygen levels) and acidosis (increased acidity). The shedding of CA IX ECD is mediated by a type of enzyme called a disintegrin and metalloproteinase (ADAM). Specifically, the study found that ADAM10, a close relative of ADAM17, can also execute the shedding of CA IX ECD.

The researchers discovered that ADAM10 cleaves CA IX ECD at a site in the stalk region of CA IX, which connects its catalytic site on the outer surface of the cell with the transmembrane region. They supported this finding through various biochemical experiments using recombinant human ADAM10 protein, examining the colocalization of ADAM10 with CA IX, and manipulating the activity of ADAM10 through the expression of a dominant-negative mutant or RNA interference-mediated suppression.

Furthermore, the study revealed that the induction of CA IX ECD cleavage can be enhanced by activators of both ADAM10 and ADAM17, showing an additive effect. Similarly, the researchers observed an additive effect when using an antibody that inhibits ADAM17 and a specific inhibitor (GI254023X) that preferentially targets ADAM10.

In summary, the study provides evidence that ADAM10 acts as a sheddase for CA IX, shedding its extracellular domain independently of ADAM17. The findings suggest that ADAM10 plays a role in regulating the functions of CA IX, such as pH regulation, metabolic reprogramming, and the promotion of migration, invasion, and metastasis in cancer cells.

Related Products

Cat.No. Product Name Information
S8660 GI254023X GI254023X (GI 4023, SRI028594) is a selective inhibitor of ADAM10 with 100-fold selectivity for ADAM10 over ADAM17. The IC50 values for recombinant ADAM10 amd ADAM17 are 5.3 nM and 541 nM, respectively.GI254023X can inhibit MMP9.

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