Cell-surface Processing of the Metalloprotease Pro-ADAMTS9 Is Influenced by the Chaperone GRP94/gp96*

By B. Koo, S. Apte. 2009

43 citations recorded by the source corpus.

A disintegrin-like and metalloprotease domain with thrombospondin type 1 motifs 9 (ADAMTS9) is a highly conserved metalloprotease that has been identified as a tumor suppressor gene and is required for normal mouse development. The secreted ADAMTS9 zymogen undergoes proteolytic excision of its N-terminal propeptide by the proprotein convertase furin. However, in contrast to other metalloproteases, propeptide excision occurs at the cell surface and leads to decreased activity of the zymogen. Here, we investigated the potential cellular mechanisms regulating ADAMTS9 biosynthesis and cell-surface processing by analysis of molecular complexes formed by a construct containing the propeptide and catalytic domain of pro-ADAMTS9 (Pro-Cat) in HEK293F cells. Cross-linking of cellular proteins bound to Pro-Cat followed by mass spectrometric analysis identified UDP-glucose:glycoprotein glucosyltransferase I, heat shock protein gp96 (GRP94), BiP (GRP78), and ERdj3 (Hsp40 homolog) as associated proteins. gp96 and BiP were present at the cell surface in an immunoprecipitable complex with pro-ADAMTS9 and furin. Treatment with geldanamycin, an inhibitor of the HSP90α family (including gp96), led to decreased furin processing of pro-ADAMTS9 and accumulation of the unprocessed pro-ADAMTS9 at the cell surface. gp96 siRNA down-regulated the levels of cell-surface pro-ADAMTS9 and furin, whereas the levels of cell-surface pro-ADAMTS9, but not of cell-surface furin, were decreased upon treatment with BiP siRNA. These data identify for the first time the cellular chaperones associated with secretion of an ADAMTS protease and suggest a role for gp96 in modulating pro-ADAMTS9 processing.

Subfields: Cancer Research, Molecular Biology

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In Cancer Research

1. S. Zhong
2. R. Khalil
3. Z. Kassiri

In Molecular Biology

1. Carlos Fernandez-Patron
2. S. Zhong
3. Pu Zhang
4. R. Khalil
5. Mengcheng Shen
6. Z. Kassiri

Citations in the corpus

• A Disintegrin and Metalloproteinase (ADAM) and ADAM with Thrombospondin Motifs (ADAMTS) Family in Vascular Biology and Disease (2019, background): “These serine proteases efficiently cleave after a consensus sequence Arg-Xaa-(Arg/Lys)-Arg, and the cleavage likely occurs in the trans-Golgi or at the cell surface [36, 37].”
• ADAMs family and relatives in cardiovascular physiology and pathology. (2016, background): “N-glycosylation within the pro-domain of ADAM-TS9 is necessary for its secretion [113].”