Identification of Novel cDNAs Encoding Human Kexin-Like Protease, PACE4 Isoforms

Tsuji, Akihiko; Higashine, K.; Hine, Chiemi; Mori, Koichi; Tamai, Y; Nagamune, Hideaki; Matsuda, Yoshiko

doi:10.1006/bbrc.1994.1541

Cited by 27 publications

(23 citation statements)

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“…Aside from the major 4.4 kb transcript, a 3.9 kb mRNA was also detected in some rat tissues such as the jejunum, duodenum and kidney [3], suggesting the presence of alternatively spliced mRNA forms of PACE4. Recent reports of Tsuji et al [10,17] suggest that an alternatively spliced human PACE4-C isoform can be isolated from human placenta. However, none of these isoforms could be detected by screening mouse liver, kidney or brain cDNA libraries [13].…”

Section: Cellular Expression Of Pace4 Isoformsmentioning

confidence: 99%

“…All of these I'Cs exhibit an N-terminal signal peptide, followed by a i,ro-segment, a catalytic domain, a P-domain and an enzyme-specific C-terminal segment [5]. Variant cDNA structures, possibly arising from alternative gene splicing, have !,een reported for PC4 [6,7], PC5 [8] and PACE4 [9,10]. In the case of PC5, the isoform PC5-A is directed to secretory !ranules while PC5-B localizes to the trans Golgi network 'Corresponding author.…”

Section: • Introductionmentioning

confidence: 95%

“…For human PACE4 four different isoforms have so far been reported; they are named PACE4-A (full length), PACE4-B (also known as PACE4.1), PACE4-C and PACE4-D [9,10]. Furthermore, as compared to human PACE4-A [9], the rat and mouse homologues [12,13] exhibit an extra Leu residue close to the predicted signal peptidase cleavage site and additionally show three deletions within the signal peptide, the N-terminal of the catalytic domain and the C-terminal segment which follows the conserved P-domain.…”

Section: • Introductionmentioning

confidence: 99%

“…Furthermore, as compared to human PACE4-A [9], the rat and mouse homologues [12,13] exhibit an extra Leu residue close to the predicted signal peptidase cleavage site and additionally show three deletions within the signal peptide, the N-terminal of the catalytic domain and the C-terminal segment which follows the conserved P-domain. From the reported importance of the pro-segment acting as an intramolecular chaperone in subtilisin-like enzymes [14], it was suggested that PACE4-D would code for an inactive enzyme [10]. Similarly, as the integrity of the P-domain has been reported to be critical for the activity of yeast kexin [15] and mouse furin [16], it was also predicted that PACE4-B, which lacks the P-domain, would be inactive [9].…”

Section: • Introductionmentioning

confidence: 99%

“…While the C-terminal border of the P-domain has been suggested to be close to Gly 631 [5,15,16], its exact site is not known with certainty and could be convertase-dependent. Therefore, it was suggested that PACE4-C could code for an active convertase [10]. Furthermore, it was reported that PACE4-C is expressed in a tissue-specific manner, based on RT-PCR [17] and immunocytochemical [18] criteria.…”

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: Cellular Expression Of Pace4 Isoformsmentioning

confidence: 99%

Section: • Introductionmentioning

confidence: 95%

Section: • Introductionmentioning

confidence: 99%

Section: • Introductionmentioning

confidence: 99%

Section: • Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 1996

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The Proprotein Convertases Furin and PACE4 Play a Significant Role in Tumor Progression

2000

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Processing of latent precursor proteins by proprotein convertases (PCs) into their biologically active products is a common mechanism required for many important biologic functions. This process is tightly regulated, leading to the generation of active peptides and proteins including neuropeptides and polypeptide hormones, protein tyrosine phosphatases, growth factors and their receptors, and enzymes including matrix metalloproteases (MMPs). These processing reactions occurs at pairs of basic amino acids. Within the past several years, a novel family of Ca2+‐dependent serine proteases has been identified, all of which possess homology to the endoproteases subtilisin (bacteria) and kexin (yeast). This family of PCs is currently comprised of fewer than a dozen members, known as furin/paired basic amino‐acid–cleaving enzyme (PACE), PC1/PC3, PC2, PC4, PACE4, PC5/PC6, and PC7/PC8/lymphoma proprotein convertase. They share a high degree of amino‐acid identity of 50–75% within their catalytic domains. Despite the relatively high degree of homology in the PC family, only PACE4 and furin localize to the same chromosome: mouse chromosome 7 and human chromosome 15. Recent reports have supported a possible functional role for PCs in tumorigenesis. For instance, convertases have been shown to be expressed in various tumor lines and human primary tumors. Furin and PACE4 process stromelysin 3 (MMP‐11 or Str‐3), an MMP involved in tumor invasion, into its mature, active form. Similarly, a growing family of MMPs, known as membrane‐type metalloproteinases (MT‐MMPs), and growth factors and adhesion molecules such as E‐cadherin show similar amino‐acid motifs and thus could be activated by furin and PACE4. These data, taken together with the high expression levels of PACE4 in 50% of murine chemically induced spindle cell tumors, confer to PACE4 and possibly other PCs a possible functional role in the activation of MMPs and consequently in tumor cell invasion and tumor progression. This was further supported by the remarkable enhancement in the invasive ability of the PACE4‐transfected murine tumor cell lines. Mol. Carcinog. 28:63–69, 2000. © 2000 Wiley‐Liss, Inc.

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Elevated furin expression in aggressive human head and neck tumors and tumor cell lines

Bassi

Mahloogi

Al-Saleem

et al. 2001

Molecular Carcinogenesis

127

114

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Pro-protein convertases (PCs) are proteases that recognize and cleave precursor proteins. Furin, a well-studied PC, is ubiquitously expressed, and it has been implicated in many physiological and pathological processes. Some substrates for furin, such as membrane type 1 (MT1) matrix metalloproteinase (MMP), an MMP that activates gelatinase, a collagen-degrading enzyme, are associated with the advanced malignant phenotype. This report examines the expression of furin in carcinoma cell lines of different invasive ability. The levels of furin mRNA and protein correlated with the aggressiveness of tumor cell lines derived from head and neck and lung cancers. Furin expression also was investigated in primary head and neck squamous cell carcinomas (HNSCCs). Furin mRNA was not detected in nonmetastasizing carcinomas. In contrast, furin mRNA was expressed in metastasizing HNSCCs. Immunohistochemistry and Western blot analysis confirmed these results at the protein level. Furin activity was investigated indirectly by evaluating the expression of the pro-form and the processed form of MT1-MMP. Metastasizing HNSCCs showed increased expression of MT1-MMP. Furthermore, pro-MT1-MMP expression was noted in most of the nonmetastasizing HNSCCs analyzed by Western blot, and it was absent in the metastasizing HNSCCs. This finding suggests a lower level of furin-mediated MT1-MMP activation in the less aggressive cancers. These observations indicate that furin plays a role in tumor progression. Its overexpression in more aggressive or metastasizing cancers resulted in increased MMP processing.

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Identification of Novel cDNAs Encoding Human Kexin-Like Protease, PACE4 Isoforms

Cited by 27 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

The Proprotein Convertases Furin and PACE4 Play a Significant Role in Tumor Progression

Elevated furin expression in aggressive human head and neck tumors and tumor cell lines

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