A Novel Member, PC7, of the Mammalian Kexin-like Protease Family - Homology to PACE4A, Its Brain-Specific Expression and Identification of Isoforms

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

doi:10.1006/bbrc.1994.2094

Cited by 24 publications

(14 citation statements)

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“…It should be noted that a previous study dating back to the late 1990s reported presumed splice variants (46,47). Many of these encoding truncated isoforms included artefactual/frameshift errors (48,49).…”

Section: Discussionmentioning

confidence: 99%

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

et al. 2017

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Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and its growth-inhibitory effects are mitigated and uncertain. Here, we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3 0 untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced autoactivating process and a distinct intracellular routing that prevented its extracellular secretion. Together, these events led to a dramatic increase in processing of the progrowth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this proenzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer. Cancer Res; 77(24); 6863-79. Ó2017 AACR.

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Section: Discussionmentioning

confidence: 99%

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

et al. 2017

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“…Other members of this family include prohormone convertase (PC)1\3 and PC2, which are restricted to neurons and endocrine cells and clearly play major roles in the biosynthetic processing of propeptides into bioactive smaller peptides, furin, which is expressed in virtually all tissues and which plays an important role in processing of proteins in the constitutive pathway (such as the insulin receptor, proendothelin, viral glycoproteins and bacterial endotoxins), PC4, which is restricted to germ cells, PC5\6, which is found in brain and gastrointestinal tissue, and LPC or PC8, which is found in all tissues [1,[5][6][7][8][9][10][11][12]. PC7 was originally used to refer to a fragment of rat PACE4 [13,14], but has recently also been used to refer to LPC\PC8 [10,12,15].…”

Section: Introductionmentioning

confidence: 99%

“…PACE4 is found at extremely high levels in most cells of the anterior pituitary and in cerebellar Purkinje cells ; the pituitary level of PACE4 mRNA is strongly responsive to thyroid status [13,14,16,17]. PACE4 is also found in the β cells of the endocrine pancreas, along with PC1, but PACE4 is absent from the α, δ and PP cells [18].…”

Section: Introductionmentioning

confidence: 99%

PACE4: a subtilisin-like endoprotease with unique properties

Mains

Berard

Denault

et al. 1997

Biochemical Journal

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PACE4 is one of the neuroendocrine-specific mammalian subtilisin-related endoproteases believed to function in the secretory pathway. The biosynthesis and secretion of PACE4 have been studied using transfected neuroendocrine and fibroblast cell lines, as well as primary pituitary cultures. ProPACE4 (approx. 106 kDa) is cleaved intracellularly before secretion of PACE4 (approx. 97 kDa); the N-terminal propeptide cleavage is accelerated in a truncated form of PACE4 lacking the Cys-rich C-terminal region (PACE4s). Neither PACE4 nor PACE4s is stored in regulated neuroendocrine secretory granules, whereas pro-opiomelanocortin-derived peptides and prohormone convertase 1 enter the regulated secretory pathway efficiently. The relatively slow cleavage of the proregion of proPACE4 in primary anterior pituitary cells, followed by rapid secretion of PACE4, is similar to the results for proPACE4 in transfected cell lines. The enzyme activity of PACE4 is distinct from furin and prohormone convertases, both in the marked sensitivity of PACE4 to inhibition by leupeptin and the relative insensitivity of PACE4 to inhibition by Ca2+ chelators and dithiothreitol; PACE4 is not inhibited by the α1-antitrypsin Portland variant that is very potent at inhibiting furin. The unique biosynthetic and enzymic patterns seen for PACE4 suggest a role for this neuroendocrine-specific subtilisin-like endoprotease outside the pathway for peptide biosynthesis.

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“…Additionally, an in vitro cleavage study of the NDV F proteins using the trans Golgi membranes of rat liver cells has revealed that the enzyme is a Ca2+-dependent and subtilisin-like serine protease (34). Amon+g seven mammalian subtilisin-like proteases cloned so far (2,39,42), furin, which distributes ubiquitously in many tissues and organs, recognizes an Arg-X-Arg/Lys-Arg motif (X denotes any amino acid) and requires Ca2+ for its activity (2,15). It is therefore a leading ca+ndidate for the processing protease of the virulent NDV F proteins.…”

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confidence: 99%

Comparison of Substrate Specificities against the Fusion Glycoprotein of Virulent Newcastle Disease Virus between a Chick Embryo Fibroblast Processing Protease and Mammalian Subtilisin‐Like Proteases

Fujii

Sakaguchi

Kiyotani

et al. 1999

Microbiology and Immunology

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The fusion (F) protein precursor of virulent Newcastle disease virus (NDV) strains has two pairs of basic amino acids at the cleavage site, and its intracellular cleavage activation occurs in a variety of cells; therefore, the viruses cause systemic infections in poultry. To explore the protease responsible for the cleavage in the natural host, we examined detailed substrate specificity of the enzyme in chick embryo fibroblasts (CEF) using a panel of the F protein mutants at the cleavage site expressed by vaccinia virus vectors, and compared the specificity with those of mammalian subtilisin-like proteases such as furin, PC6 and PACE4 which are candidates for F protein processing enzymes. It was demonstrated in CEF cells that Arg residues at the -4, -2 and -1 positions upstream of the cleavage site were essential, and that at the -5 position was required for maximal cleavage. Phe at the +1 position was also important for efficient cleavage. On the other hand, furin and PC6 expressed by vaccinia virus vectors showed cleavage specificities against the F protein mutants consistent with that shown by the processing enzyme of CEF cells, but PACE4 hardly cleaved the F proteins including the wild type. These results indicate that the proteolytic processing enzymes of poultry for virulent NDV F proteins could be furin and/or PC6 but not PACE4. The significance of individual contribution of the three amino acids at the -5, -2 and +1 positions to cleavability was discussed in relation to the evolution of virulent and avirulent NDV strains.

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A Novel Member, PC7, of the Mammalian Kexin-like Protease Family - Homology to PACE4A, Its Brain-Specific Expression and Identification of Isoforms

Cited by 24 publications

References 0 publications

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

PACE4: a subtilisin-like endoprotease with unique properties

Comparison of Substrate Specificities against the Fusion Glycoprotein of Virulent Newcastle Disease Virus between a Chick Embryo Fibroblast Processing Protease and Mammalian Subtilisin‐Like Proteases

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