Intracellular Processing of Metalloprotease Disintegrin ADAM12*

By Yi Cao, Q. Kang, Zhefeng Zhao, A. Zolkiewska. 2002

69 citations recorded by the source corpus.

ADAM12 has been implicated in cell-cell interactions in myogenesis and cancer, but the structure of the mature form of ADAM12 is not known, and its localization on the cell surface has been questioned. In this report, we show that full-length ADAM12 isN-glycosylated in the endoplasmic reticulum (ER) and proteolytically processed in the trans-Golgi network to an ∼90-kDa form. The ∼90-kDa form, which lacks the prodomain, was the predominant form present at the cell surface. Replacement of Leu73 in the putative α-helical region in the prodomain with proline resulted in retention of ADAM12 in the ER and a complete lack of its processing. However, deletion of the entire pro- and metalloprotease domains did not affect the processing and trafficking of ADAM12. In contrast, replacement of the cytoplasmic domain of ADAM12 with that of ADAM9 or adding a c-Myc tag at the C terminus led to a significant increase in transport of the protein to the cell surface. These results suggest that the cytoplasmic domain of ADAM12 plays an important role in regulating ADAM12 exit from the ER. We conclude that properly folded mouse ADAM12, after passing a rate-limiting step of exit from the ER, is processed in the secretory pathway and reaches the cell surface, where it can mediate adhesion-mediated signaling.

Subfields: Immunology and Allergy, Oncology

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Citations in the corpus

A Disintegrin and Metalloproteinase (ADAM) and ADAM with Thrombospondin Motifs (ADAMTS) Family in Vascular Biology and Disease (2019, background): “Therefore, the pro-domain removing procedure is not necessary for ADAM-12 activation, and ADAM-12 can still conserve its function without proteolytic processing which is crucial for other ADAMs [30].”
ADAMs family and relatives in cardiovascular physiology and pathology. (2016, background): “Deletion of the entire pro- and metalloprotease domains in ADAM12 did not affect the processing and trafficking of this ADAM [31].”
The ADAM metalloproteinases (2008, background): “Second, there are now clear examples where the cytoplasmic domain plays a key role in ADAM function, either by regulating catalytic activity or by trafficking the protein to the correct cellular location (Cao et al., 2002).”