Secretory proprotein convertases PACE4 and PC6A are heparin-binding proteins which are localized in the extracellular matrix

Tsuji, Akihiko; Sakurai, Kensuke; Kiyokage, Emi; Yamazaki, Takahito; Koide, S.S.; Toida, Kazunori; Ishimura, Kazunori; Matsuda, Yoshiko

doi:10.1016/s1570-9639(02)00532-0

Cited by 80 publications

(75 citation statements)

References 57 publications

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“…Interestingly, the two SPC family members PACE4 (SPC4) and PC6A were detected attached to heparin residues of heparan sulfate proteoglycans in the extracellular matrix of HEK293 cells (28). This may be of relevance since heparan sulfate containing proteoglycans are abundant in cartilage matrix and thus may represent a source of SPCs responsible for cleavage of Ucma in vivo (29).…”

Section: Discussionmentioning

confidence: 96%

Ucma, a Novel Secreted Cartilage-specific Protein with Implications in Osteogenesis

Surmann‐Schmitt

Dietz

Kireva

et al. 2008

Journal of Biological Chemistry

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Here we report on the structure, expression, and function of a novel cartilage-specific gene coding for a 17-kDa small, highly charged, and secreted protein that we termed Ucma (unique cartilage matrix-associated protein). The protein is processed by a furin-like protease into an N-terminal peptide of 37 amino acids and a C-terminal fragment (Ucma-C) of 74 amino acids. Ucma is highly conserved between mouse, rat, human, dog, clawed frog, and zebrafish, but has no homology to other known proteins. Remarkable are 1-2 tyrosine sulfate residues/molecule and dense clusters of acidic and basic residues in the C-terminal part. In the developing mouse skeleton Ucma mRNA is expressed in resting chondrocytes in the distal and peripheral zones of epiphyseal and vertebral cartilage. Ucma is secreted into the extracellular matrix as an uncleaved precursor and shows the same restricted distribution pattern in cartilage as Ucma mRNA. In contrast, antibodies prepared against the processed C-terminal fragment located Ucma-C in the entire cartilage matrix, indicating that it either diffuses or is retained until chondrocytes reach hypertrophy. During differentiation of an MC615 chondrocyte subclone in vitro, Ucma expression parallels largely the expression of collagen II and decreases with maturation toward hypertrophic cells. Recombinant Ucma-C does not affect expression of chondrocyte-specific genes or proliferation of chondrocytes, but interferes with osteogenic differentiation of primary osteoblasts, mesenchymal stem cells, and MC3T3-E1 pre-osteoblasts. These findings suggest that Ucma may be involved in the negative control of osteogenic differentiation of osteochondrogenic precursor cells in peripheral zones of fetal cartilage and at the cartilage-bone interface.Elucidation of molecular mechanisms underlying chondrocyte differentiation is not only important for our understanding of skeletal development, but also of particular interest for our knowledge on the behavior of chondrocytes following articular cartilage damage during cartilage repair and treatment of degenerative cartilage diseases. Initial steps of chondrogenesis, i.e. the formation of a cartilage blastema from limb bud mesenchymal cells, include cell condensation and onset of chondrocyte differentiation marked by the expression of cartilage-specific matrix proteins such as aggrecan, collagen II, IX, and XI and others (1, 2). These events are regulated by the orchestrated action of several growth factors including BMPs, Wnt factors, FGFs, and the transcription factors Sox5,6, and 9 (3,4). Further steps of chondrocyte growth, maturation, and replacement by bone in the growth plate of long bones, ribs, and vertebrae during endochondral ossification can be defined by the stepwise onset or decline of differentially expressed genes: collagen II and Sox9 for resting and proliferating, FGFR3 for proliferating and prehypertrophic, Ihh and PTHrP receptor for prehypertrophic, collagen X for hypertrophic, and Runx2, osteocalcin, and MMP13 for late hypertrophic chondrocytes (...

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Section: Discussionmentioning

confidence: 96%

Ucma, a Novel Secreted Cartilage-specific Protein with Implications in Osteogenesis

Surmann‐Schmitt

Dietz

Kireva

et al. 2008

Journal of Biological Chemistry

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“…It is likely, therefore, that distinct polarized secretion also accounts for the differential distribution of extracellular Furin and Pace4 in the embryo. Unlike Furin, Pace4 contains a cysteinerich repeat region that mediates high-affinity binding to HSPGs (Tsuji et al 2003;Nour et al 2005;Mayer et al 2008). HSPGs in general are sorted basolaterally (Mertens et al 1996;Tveit et al 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Pace4 is soluble by default and enriched in extracellular matrix by heparan sulfate proteoglycans (HSPGs) (Tsuji et al 2003;Mayer et al 2008). In contrast, Furin has a transmembrane domain and binds cytosolic adapters that mediate cycling between the trans-Golgi network, the cell surface, and endosomes (Thomas 2002).…”

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confidence: 99%

The microenvironment patterns the pluripotent mouse epiblast through paracrine Furin and Pace4 proteolytic activities

Mesnard¹,

Donnison²,

Fuerer³

et al. 2011

Genes Dev.

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The fate of pluripotent cells in early mouse embryos is controlled by graded Nodal signals that are activated by the endoproteases Furin and Pace4. Soluble forms of Furin and Pace4 cleave proNodal in vitro and after secretion in transfected cells, but direct evidence for paracrine activity in vivo is elusive. Here, we show that Furin and Pace4 are released by the extraembryonic microenvironment, and that they cleave a membrane-bound reporter substrate in adjacent epiblast cells and activate Nodal to maintain pluripotency. Secreted Pace4 and Furin also stimulated mesoderm formation, whereas endoderm was only induced by Pace4, correlating with a difference in the spatiotemporal distribution of these proteolytic activities. Our analysis of paracrine Furin and Pace4 activities and their in vivo functions significantly advances our understanding of how the epiblast is patterned by its microenvironment. Adding cell-cell communication to the pleiotropic portfolio of these proteases provides a new framework to study proprotein processing also in other relevant contexts.

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“…Molecular shedding events that take place at the cell surface are mostly attributable to PC-activated cell-surface proteases such as the ADAMs and membrane-type-MMPs (44,45). Furin is known to exist at the cell surface (19,46) and other PCs such as PACE4 and PC6/5A are known to be secreted and anchored in the extracellular matrix (47) and are therefore presumed to have extracellular substrates. Protective antigens of anthrax and diphtheria toxin are cleaved at consensus furin cleavage sites on the exterior of the cell, as well as in intracellular organelles (20,22).…”

Section: Discussionmentioning

confidence: 99%

Cell-surface Processing of Pro-ADAMTS9 by Furin

Koo

Longpré

Somerville

et al. 2006

Journal of Biological Chemistry

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Processing of polypeptide precursors by proprotein convertases (PCs) such as furin typically occurs within the trans-Golgi network.Here, we show in a variety of cell types that the propeptide of ADAMTS9 is not excised intracellularly. Pulse-chase analysis in HEK293F cells indicated that the intact zymogen was secreted to the cell surface and was subsequently processed there before release into the medium. The processing occurred via a furin-dependent mechanism as shown using PC inhibitors, lack of processing in furindeficient cells, and rescue by furin in these cells. Moreover, down-regulation of furin by small interference RNA reduced ADAMTS9 processing in HEK293F cells. PC5A could also process pro-ADAMTS9, but similarly to furin, processed forms were absent intracellularly. Cellsurface, furin-dependent processing of pro-ADAMTS9 creates a precedent for extracellular maturation of endogenously produced secreted proproteins. It also indicates the existence of a variety of mechanisms for processing of ADAMTS proteases.Zinc metalloendopeptidases, like most proteases, are synthesized as zymogens, and the N-terminal propeptide is usually excised. Propeptide excision usually leads to enzymatic activation, an important regulatory event, and it can occur intracellularly, at the cell surface, or extracellularly through a variety of proteolytic mechanisms. In one such mechanism, the propeptide is proteolytically excised by serine proteases of the mammalian subtilisin-like proprotein convertase (PC) 4 family (1-5). This mechanism is used by some MMPs (6, 7), many ADAMs (8 -10), and all ADAMTS proteases studied thus far (11,12). In these proteases, removal of the propeptide appears to be mediated by the most widely distributed PC, furin, and occurs within the constitutive secretory pathway, specifically in the trans-Golgi network (TGN) (7-9, 13, 14).Furin is the best studied of the seven PCs implicated in proprotein processing within the constitutive secretory pathway, and it is present in virtually all cells (1, 15). It is a type I transmembrane protein that is itself synthesized as a zymogen that undergoes autocatalytic intramolecular activation (16). Furin cleaves on the carboxyl side of a consensus recognition site that is rich in basic residues (e.g. Arg-Xaa-Arg/Lys-Arg2) (2,4,5,17). Most furin resides in the TGN, but some is present at the plasma membrane and shuttles between the cell surface and the . Furin is also shed from cells and may be functional in the extracellular space (21). Microbial toxins such as the anthrax protective antigen and diphtheria toxin are processed by cell-surface furin, with important implications for their toxicity (20,22). However, the physiological role of cell-surface or secreted furin in processing endogenous cellular products has remained elusive.The ADAMTS proteases are a family of 19 secreted enzymes, of which some have critical physiological functions and have been implicated in inherited human disorders, namely Ehlers-Danlos syndrome type VIIC (ADAMTS2), Weill-Marchesani syndrom...

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Secretory proprotein convertases PACE4 and PC6A are heparin-binding proteins which are localized in the extracellular matrix

Cited by 80 publications

References 57 publications

Ucma, a Novel Secreted Cartilage-specific Protein with Implications in Osteogenesis

Ucma, a Novel Secreted Cartilage-specific Protein with Implications in Osteogenesis

The microenvironment patterns the pluripotent mouse epiblast through paracrine Furin and Pace4 proteolytic activities

Cell-surface Processing of Pro-ADAMTS9 by Furin

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