Proteolytic Processing Mechanisms in the Biosynthesis of Neuroendocrine Peptides: The Subtilisin-like Proprotein Convertases

Rouillé, Yves; Duguay, Stephen J.; Lund, Kaare; Furuta, Machi; Gong, Qiuming; Lipkind, Gregory M.; Oliva, Anthony A.; Chan, Shu Jin; Steiner, Donald F.

doi:10.1006/frne.1995.1012

Cited by 336 publications

(296 citation statements)

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“…). Intriguingly, a recent report suggested that PACE4-C imnunoreactivity could be detected in rat pancreatic [3-cells [18], vhich are also known to express PC1 and PC2 [2,32]. Furthernore, the authors claim that PACE4-A immunoreactivity was mdetectable in pancreatic islets [18].…”

Section: Discussionmentioning

confidence: 98%

“…The role of the PCs in the generation of such diversity is now well accepted and is the subject of intense study aimed at defining the specific role of each of the seven known convertases in this process [1][2][3][4][5]. Another level of diversity can also be achieved by alternative splicing of either the proprotein substrate or its cognate convertase(s).…”

Section: Discussionmentioning

confidence: 99%

“…Processing of proproteins and prohormones at either single • ,r pairs of basic residues is a general mechanism to generate t,ioactive proteins and peptides from inactive precursors [1,2]. "he subtilisin/kexin-like proteinases responsible for such int racellular cleavages have recently been described and are alled 'proprotein convertases' (PCs).…”

Section: • Introductionmentioning

confidence: 99%

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Functional analysis of human PACE4‐A and PACE4‐C isoforms: identification of a new PACE4‐CS isoform

et al. 1996

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There are seven known subtilisin/kexin-like proprorein convertases responsible for the processing of numerous precursors at either pairs or specific single basic residues. Three members, PACEA, PC4 and PC5, exhibit alternative splicing of their RNAs resulting in the generation of multiple isoforms differing in their C-or N-terminal segments. In this study we t~xamined the biosynthesis, functional activity and cellular localization of two of these isoforms, namely the full length PACE4-A and the C-terminally truncated PACE4-C which lacks 11 amino acids at the end of its chaperone-like P-domain. We report the existence of a new isoform, termed PACE4-CS, which is a C-terminally shortened version of PACE4-C. Cellular expression results demonstrated that PACE4-A codes for a functional secretable enzyme capable of cleaving pro7B2 into 7B2. In contrast, PACE4-CS is not secreted since it remains in the endoplasmic reticulum as an inactive zymogen form, thereby emphasizing the importance of the integrity of the P-domain. Vlicrosequencing of the intracellular PACE4-CS protein in two cell lines revealed that it is proPACE4-CS with an N-terminal trimming reminiscent of the action of a dipeptidyipeptidase recognizing the motifs X-Ala and X-Pro.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: • Introductionmentioning

confidence: 99%

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Functional analysis of human PACE4‐A and PACE4‐C isoforms: identification of a new PACE4‐CS isoform

et al. 1996

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“…Although, several enzymes are involved in the metabolism of the protachykinin-1 protein and tachykinin peptides, including neutral endopeptidase [12] and angiotensin converting enzyme [13], the role of proprotein convertases (PCs) remains unclear. It has been widely demonstrated that several neuropeptides are synthesized by the actions of PCs and specific endopeptidases [11,12,14,15]. Comprehensive studies demonstrated that PC1 and PC2 recognize motives composed of either a pair of basic amino acids (KR-, RR-, RK-and KK-), or a single residue (R or K) [16,17].…”

Section: Introductionmentioning

confidence: 99%

Tachykinins Processing is Significantly Impaired in PC1 and PC2 Mutant Mouse Spinal Cord S9 Fractions

et al. 2015

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“…In addition, we recently showed that immune cells express large amounts of both furin and PC7 [9][10][11]. In contrast, PCI, PC2 [9,12,13] and possibly PC5-A [14] are responsible for precursor processing within the regulated secretory pathway, mainly in endocrine and neural cells. PC4 is specific to testicular germ cells [15].…”

Section: Introductionmentioning

confidence: 99%

Comparative processing of bovine leukemia virus envelope glycoprotein gp72 by subtilisin/kexin‐like mammalian convertases

et al. 1997

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Intracellular proteolytic processing of bovine leukemia virus (BLV) envelope glycoprotein precursor (gp72) at the Cterminal end of the RVRR 268 J, site is an essential step for virus infectivity. Subtilisin/kexin-like convertases cleave proproteins at preferred RX(K/R)R J, sites, including those commonly found in viral envelope glycoprotein precursors. We first demonstrated that gp72 is processed into gp51/gp30 in both CV1 cells and the furin-deficient LoVo cells, leading us to compare the ability of mammalian convertases to cleave BLV gp72 in vitro. In contrast to the inability of the neuroendocrine PCI to cleave gp72, the convertases furin, PACE4, PC5-A and PC5-B, which process constitutively secreted precursors, can effectively cleave gp72 into gp51/gp30. N-terminal sequence analysis of the convertasegenerated gp30 demonstrated that cleavage occurs at the in vivoutilized RVRRiSPV site. Such furin-, PACE4-and PC5-mediated processing was completely inhibited by the oiiantitrypsin variant od-PDX. Mutagenesis of the gp72 cleavage site into RVRG-TPV resulted in complete abrogation of gp72 processing by endogenous CV-1 cells and by convertases in vitro. Since our in vitro data suggest a redundancy in the ability of the convertases to cleave gp72, RT-PCR analysis was used to define the convertases expressed in B-lymphocytes, representing one of the major targets of BLV infection. Our data revealed that only furin and the newly discovered PC7 mRNAs are expressed in Raji, B-Jab and LG2 cell lines.

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Proteolytic Processing Mechanisms in the Biosynthesis of Neuroendocrine Peptides: The Subtilisin-like Proprotein Convertases

Cited by 336 publications

References 0 publications

Functional analysis of human PACE4‐A and PACE4‐C isoforms: identification of a new PACE4‐CS isoform

Functional analysis of human PACE4‐A and PACE4‐C isoforms: identification of a new PACE4‐CS isoform

Tachykinins Processing is Significantly Impaired in PC1 and PC2 Mutant Mouse Spinal Cord S9 Fractions

Comparative processing of bovine leukemia virus envelope glycoprotein gp72 by subtilisin/kexin‐like mammalian convertases

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