ArticleThe Biochemical journal2003
Processing of alpha4 integrin by the proprotein convertases: histidine at position P6 regulates cleavage.
Article in The Biochemical journal, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 56 citations in OpenAlex.
- Review
- Selective inhibition of N-linked glycosylation impairs receptor tyrosine kinase processing.Disease models & mechanisms · 2019Article
- Enhanced UV-induced skin carcinogenesis in transgenic mice overexpressing proprotein convertases.Neoplasia (New York, N.Y.) · 2013Article
- Transgenic overexpression of the proprotein convertase furin enhances skin tumor growth.Neoplasia (New York, N.Y.) · 2012Article
- A systematic study of site-specific GalNAc-type O-glycosylation modulating proprotein convertase processing.The Journal of biological chemistry · 2011Article
- Short form of α9 promotes α9β1 integrin-dependent cell adhesion by modulating the function of the full-length α9 subunit.Experimental cell research · 2011Article
- An integrin alpha4beta7•IgG heterodimeric chimera binds to MAdCAM-1 on high endothelial venules in gut-associated lymphoid tissue.The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2011Article
- Processing of proaugurin is required to suppress proliferation of tumor cell lines.Molecular endocrinology (Baltimore, Md.) · 2011Article
- Zebrafish ProVEGF-C expression, proteolytic processing and inhibitory effect of unprocessed ProVEGF-C during fin regeneration.PloS one · 2010Article
- Article
- Comparative study of the binding pockets of mammalian proprotein convertases and its implications for the design of specific small molecule inhibitors.International journal of biological sciences · 2010Article
- The proprotein convertase PC5/6 is protective against intestinal tumorigenesis: in vivo mouse model.Molecular cancer · 2009Article
- Processing of peptide and hormone precursors at the dibasic cleavage sites.Cellular and molecular life sciences : CMLS · 2009Review
- Genetically determined proteolytic cleavage modulates alpha7beta1 integrin function.The Journal of biological chemistry · 2008Article
- Differential modulation of prM cleavage, extracellular particle distribution, and virus infectivity by conserved residues at nonfurin consensus positions of the dengue virus pr-M junction.Journal of virology · 2008Article
- Cell-surface processing of extracellular human immunodeficiency virus type 1 Vpr by proprotein convertases.Virology · 2008Article
- The proprotein convertases are potential targets in the treatment of dyslipidemia.Journal of molecular medicine (Berlin, Germany) · 2007Review
- Identification of a pH sensor in the furin propeptide that regulates enzyme activation.The Journal of biological chemistry · 2006Article
- Deletion of the gene encoding proprotein convertase 5/6 causes early embryonic lethality in the mouse.Molecular and cellular biology · 2006Article
- The cysteine-rich domain of the secreted proprotein convertases PC5A and PACE4 functions as a cell surface anchor and interacts with tissue inhibitors of metalloproteinases.Molecular biology of the cell · 2005Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The proprotein convertases (PCs) participate in the limited proteolysis of integrin alpha4 subunit at the H(592)VISKR(597) downward arrow ST site (where underlined residues indicate positively charged amino acids important for PC-mediated cleavage and downward arrow indicates the cleavage site), since this cleavage is inhibited by the serpin alpha1-PDX (alpha1-antitrypsin Portland). Co-expression of alpha4 with each convertase in LoVo (furin-deficient human colon carcinoma) cells revealed that furin and proprotein convertase 5A (PC5A) are the best pro-alpha4 convertases. In agreement, processing of endogenous pro-alpha4 in human lymphoblastoid CEM-T4 cells was enhanced greatly in stable transfectants overexpressing either enzyme. In many leucocyte cell lines, the expression of furin closely correlated with the endogenous processing efficacy, suggesting that furin is a candidate pro-alpha4 convertase. Mutational analysis showed that replacement of P1 Arg(597) with alanine (R597A) abrogated cleavage, whereas the P6 mutant H592R is even better processed by the endogenous convertases of Chinese-hamster ovary CHO-K1 cells. In vitro kinetic studies using synthetic peptides confirmed the importance of a positively charged residue at P6 and showed that wild-type alpha4 processing is performed best by furin and PC5A at acidic and neutral pHs, respectively. Biosynthetic analysis of pro-alpha4 and its H592R and H592K mutants in the presence or absence of the weak base, NH(4)Cl, revealed that the P6 histidine residue renders its processing by furin sensitive to cellular pH. This suggests that pro-alpha4 cleavage occurs preferentially in acidic compartments. In conclusion, although the accepted furin processing motif is Arg-Xaa-(Lys/Arg)-Arg downward arrow, our data further extend it to include a regulatory histidine residue at P6 in precursors that lack a basic residue at P4.
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