Proteolytic Processing in the Secretory Pathway

Zhou, An; Webb, Gene C.; Zhu, Xiaorong; Steiner, Donald F.

doi:10.1074/jbc.274.30.20745

Cited by 453 publications

(440 citation statements)

References 107 publications

(87 reference statements)

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“…CPE removes COOH-terminal basic residues of peptide intermediates generated by proteolytic processing of proneuropeptides by the subtilisin-like prohormone convertases 1 and 2 (PC 1/3 and PC 2) [3][4][5]. Thus, both aminopeptidase and carboxypeptidase metallopeptidases are involved in secretory vesicle production of neuropeptides.…”

Section: Discussionmentioning

confidence: 99%

Zinc regulation of aminopeptidase B involved in neuropeptide production

Hwang

Hook

2008

FEBS Letters

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Aminopeptidase B (AP-B) is a metallopeptidase that removes basic residues from the N-termini of neuropeptide substrates in secretory vesicles. This study assessed zinc regulation of AP-B activity, since secretory vesicles contain endogenous zinc. AP-B was inhibited by zinc at concentrations typically present in secretory vesicles. Zinc effects were dependent on concentration, incubation time, and the molar ratio of zinc to enzyme. AP-B activity was recovered upon removal of zinc. AP-B with zinc became susceptible to degradation by trypsin, suggesting that zinc alters enzyme conformation. Zinc regulation demonstrates the metallopeptidase property of AP-B.

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Section: Discussionmentioning

confidence: 99%

Zinc regulation of aminopeptidase B involved in neuropeptide production

Hwang

Hook

2008

FEBS Letters

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“…Indeed, although previously unrecognized, an overlapping "triplet" of minimal proprotein convertase recognition motifs is embedded in the 86 KAMRRPR peptide as 86 KXXR, 89 RXXR, or 89 RR (Figure 1) (Zhou et al, 1999). To simultaneously eliminate all three sites, an R 89 3 A substitution was inserted in either wildtype MT1-MMP (i.e., MT1-MMP/AXXR) or MT1-MMP/A4 (i.e., MT1-MMP/AXXR-A4).…”

Section: Mt1-mmp Activationmentioning

confidence: 99%

“…Four members of the proprotein convertase family, i.e., furin, PACE4, PC6, and PC7, have been implicated in the processing of target molecules in the constitutive secretory pathway (Zhou et al, 1999). ␣ 1 PDX is an engineered mutant of ␣ 1 proteinase inhibitor in which the active site loop has been altered to display an Arg-X-X-Arg motif that acts specifically as a bait region for the proprotein convertases furin and PC6 Cui et al, 1998;Jean et al, 1998).…”

Section: ␣ 1 Pdx Blocks Promt1-mmp Processingmentioning

confidence: 99%

“…To determine if furin, a ubiquitously expressed proprotein convertase, plays a predominant role in the ␣ 1 PDX-sensitive maturation of proMT1-MMP, the processing of the proteinase was examined in two furin-deficient cell lines, LoVo and RPE.40 (Inocencio et al, 1997;Zhou et al, 1999). Significantly, LoVo was unable to process soluble ⌬MT1-MMP unless cotransfected with the furin cDNA ( Figure 4A, lanes 1-3).…”

Section: Mt1-mmp Processing and Activity In Furindeficient Cell Linesmentioning

confidence: 99%

“…Interestingly, MT1-MMP contains a similar 108 RRKR motif upstream of the N terminus of its mature form (Sato et al, 1994;Nagase and Woessner, 1999). Because RX(K/R)R sequences can act as general recognition motifs for at least four members of the proprotein convertase family, i.e., furin, PACE4, PC6, and PC7 (Nakayama, 1997;Zhou et al, 1999), the MT1-MMP zymogen could present itself as a substrate for these processing enzymes.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Membrane Type-1 Matrix Metalloproteinase Activation by Proprotein Convertases

Yana

Weiss

2000

MBoC

278

271

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Membrane type-1 matrix metalloproteinase (MT1-MMP) is the prototypical member of a subgroup of membrane-anchored proteinases that belong to the matrix metalloproteinase family. Although synthesized as a zymogen, MT1-MMP plays an essential role in extracellular matrix remodeling after an undefined process that unmasks its catalytic domain. We now report the existence of a proprotein convertase-MT1-MMP axis that regulates the processing and functional activity of the metalloproteinase. Two sets of basic motifs in the propeptide region of MT1-MMP are identified that potentially can be recognized by the proprotein convertase family of subtilisinlike proteases. Processing of proMT1-MMP as well as the expression of its proteolytic activity were blocked by mutating these recognition motifs or by inhibiting the proprotein convertases furin and PC6 with the serpin-based inhibitor ␣ 1 antitrypsin Portland. Furthermore, both furindependent and furin-independent MT1-MMP processing pathways are identified that require tethering of the metalloproteinase to the cell surface. These findings demonstrate the existence of a proprotein convertase-MT1-MMP axis that can regulate extracellular matrix remodeling.

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Insulin

Steiner

2002

Wiley Encyclopedia of Molecular Medicine

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Proteolytic Processing in the Secretory Pathway

Cited by 453 publications

References 107 publications

Zinc regulation of aminopeptidase B involved in neuropeptide production

Zinc regulation of aminopeptidase B involved in neuropeptide production

Regulation of Membrane Type-1 Matrix Metalloproteinase Activation by Proprotein Convertases

Insulin

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