Proprotein Convertase PC7 Enhances the Activation of the EGF Receptor Pathway through Processing of the EGF Precursor

Abstract

Although the processing profile of the membrane-bound epidermal growth factor precursor (pro-EGF) is tissue-specific, it has not been investigated at the cellular level nor have the cognate proteinases been defined. Among the proprotein convertases (PCs), only the membrane-bound PC7, the most ancient and conserved basic amino acid-specific PC family member, induces the processing of pro-EGF into an ϳ115-kDa transmembrane form (EGF-115) at an unusual VHPR 290 2A motif. Because sitedirected mutagenesis revealed that Arg 290 is not critical, the generation of EGF-115 by PC7 is likely indirect. This was confirmed by testing a wide range of protease inhibitors, which revealed that the production of EGF-115 is most probably achieved via the activation by PC7 of a latent serine and/or cysteine protease(s). EGF-115 is more abundant at the cell surface than pro-EGF and is associated with a stronger EGF receptor (EGFR) activation, as evidenced by higher levels of phosphorylated ERK1/2. This suggests that the generation of EGF-115 represents a regulatory mechanism of juxtacrine EGFR activation. Thus, PC7 is distinct from the other PCs in its ability to enhance the activation of the cell surface EGFR.

Proprotein Convertase Subtilisin/Kexin Type 7 (PCSK7) Is Essential for the Zebrafish Development and Bioavailability of Transforming Growth Factor β1a (TGFβ1a)

“…10) (44). However, it is equally probable that in vivo PCSK7 promotes the TGF␤1a function in an indirect manner that does not involve direct proteolysis (21).…”

“…For example, the activity of PCSK7 can be replaced in the site-specific cleavage of pro-BMP4 (15), pro-PDGF (16), pro-NGF (17,18), and pro-VEGF-C (19). However, PCSK7 seems to be solely responsible for rescuing an unstable MHC I in post-endoplasmic reticulum compartments (20) and for the proteolysis of pro-EGF (21). In addition, a genome-wide association study recently revealed that an SNP (rs236918) in the PCSK7 gene region is associated with an increase in the serum level of soluble transferrin receptor, thus implying that PCSK7 could have a role in iron metabolism in humans (22).…”

Furin Is the Major Processing Enzyme of the Cardiac-specific Growth Factor Bone Morphogenetic Protein 10

“…Thus, pro-BMP10 processing requires membrane association of furin. The intracellular cleavage of pro-BMP10 by furin was further confirmed by the inability of D6R to inhibit the pro-BMP10 processing in CHO-FD11 overexpressing either furin CT-PC7 or furin TMCT-PC7 (not shown), although the latter chimera is mostly localized at the cell surface (34).…”

Internalization of Proprotein Convertase PC7 from Plasma Membrane Is Mediated by a Novel Motif

“…It has been demonstrated that PC7 reaches the cell surface via the conventional route as well as via a brefeldin A-and coat protein complex II (COPII)-independent unconventional secretory pathway (12). Furthermore, it has been suggested that pro-EGF processing by full-length membrane-bound PC7 does not occur at the cell surface but that it requires endocytosis into clathrin-coated pits (29). In this study, the endocytosis of PC7 from the plasma membrane was investigated by means of cell fractionation, antibody uptake experiments, and cell surface biotinylation.…”