BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development

Cui, Yanzhen; Jean, François; Thomas, Gary; Christian, Jan L.

doi:10.1093/emboj/17.16.4735

Cited by 215 publications

(162 citation statements)

References 48 publications

(63 reference statements)

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“…Alternatively, the secondary structure of Xlefty, or the inherent protease sensitivity at each site, may differ between oocytes and embryonic tissues, such that CS2 cleavage does not occur in embryonic tissues. A general conclusion from our studies, therefore, despite the numerous reported experiments using Xenopus oocytes to infer the mechanisms regulating the biochemical processing of secreted proproteins (Dale et al, 1989;Thomsen and Melton, 1993;Jones et al, 1996;Cui et al, 1998Cui et al, , 2001Eimon and Harland, 2002;Degnin et al, 2004), is that only embryonic cells should be used for future studies of Xlefty.…”

Section: Cleavage Of Xlefty Is Required To Block Xnr Signaling But Nomentioning

confidence: 76%

“…SPCs may, therefore, work in both a cellautonomous and non-cell-autonomous manner (Nakayama, 1997;Molloy et al, 1999). SPC-mediated cleavage releases the active ligand during the maturation of TGF␤ proteins (Kingsley, 1994;Nakayama, 1997;Cui et al, 1998;Constam and Robertson, 1999;Molloy et al, 1999;Ulloa et al, 2001;Beck et al, 2002;Sakuma et al, 2002;Ben-Haim et al, 2006). Although mammalian Lefty molecules have been shown to undergo proteolytic cleavage by SPC1, SPC4, and SPC6 in several transfected cell lines, the endogenous SPC enzyme(s) that is involved in proteolytic processing of Lefty in vivo is currently not known (Ulloa et al, 2001;Beck et al, 2002;Sakuma et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Xenopus Lefty requires proprotein cleavage but not N‐linked glycosylation to inhibit nodal signaling

Westmoreland

Takahashi

Wright

2007

Developmental Dynamics

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The Nodal and Nodal-related morphogens are utilized for the specification of distinct cellular identity throughout development by activating discrete target genes in a concentration-dependant manner. Lefty is a principal extracellular antagonist involved in the spatiotemporal regulation of the Nodal morphogen gradient during mesendoderm induction. The Xenopus Lefty proprotein contains a single N-linked glycosylation motif in the mature domain and two potential cleavage sites that would be expected to produce long (Xlefty L ) and short (Xlefty S ) isoforms. Here we demonstrate that both isoforms were secreted from Xenopus oocytes, but that Xlefty L is the only isoform detected when embryonic tissue was analyzed. In mesoderm induction assays, Xlefty L is the functional blocker of Xnr signaling. When secreted from oocytes, vertebrate Lefty molecules were N-linked glycosylated. However, glycan addition was not required to inhibit Xnr signaling and did not influence its movement through the extracellular space. These findings demonstrate that Lefty molecules undergo post-translational modifications and that some of these modifications are required for the Nodal inhibitory function.

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Section: Cleavage Of Xlefty Is Required To Block Xnr Signaling But Nomentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Xenopus Lefty requires proprotein cleavage but not N‐linked glycosylation to inhibit nodal signaling

Westmoreland

Takahashi

Wright

2007

Developmental Dynamics

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“…38 Besides TGF-b1 furin cleaves for example b-nerve growth factor, bone morphogenetic protein-4, membrane-type 1 matrix metalloproteinase, the a-and b-secretases associated with Alzheimer's disease and bacterial toxins. [42][43][44] Cleavage of these substrates occurs at the TGN but is not limited to this compartment. Furin cycles between the TGN and the cell surface, where it can process different substrates.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

Wottawa

Leisering

Ahlen

et al. 2012

Intl Journal of Cancer

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The prolyl-4-hydroxylase domain 1-3 (PHD1-3) enzymes are regulating the protein stability of the a-subunit of the hypoxiainducible factor-1 (HIF-1), which mediates oxygen-dependent gene expression. PHD2 is the main isoform regulating HIF-1a hydroxylation and thus stability in normoxia. In human cancers, HIF-1a is overexpressed as a result of intratumoral hypoxia which in turn promotes tumor progression. The role of PHD2 for tumor progression is in contrast far from being thoroughly understood. Therefore, we established PHD2 knockdown clones of MDA-MB-231 breast cancer cells and analyzed their tumorforming potential in a SCID mouse model. Tumor progression was significantly impaired in the PHD2 knockdown MDA-MB-231 cells, which could be partially rescued by re-establishing PHD2 expression. In a RNA profile screen, we identified the secreted phosphoprotein 1 (SPP1) as one target, which is differentially regulated as a consequence of the PHD2 knockdown. Knockdown of PHD2 drastically reduced the SPP1 expression in MDA-MB-231 cells. A correlation of SPP1 and PHD2 expression was additionally verified in 294 invasive breast cancer biopsies. In subsequent analyses, we identified that PHD2 alters the processing of transforming growth factor (TGF)-b1, which is highly involved in SPP1 expression. The altered processing capacity was associated with a dislocation of the pro-protein convertase furin. Thus, our data demonstrate that in MDA-MB-231 cells PHD2 might affect tumor-relevant TGF-b1 target gene expression by altering the TGF-b1 processing capacity.

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“…MT1-MMP processing was unaffected by serine (aprotinin, soybean trypsin inhibitor), cysteine (E-64), or aspartate (pepstatin A) proteinase inhibitors (our unpublished results). Based on the substrate specificity of ␣ 1 PDX (Cui et al, 1998;Jean et al, 1998), we conclude that furin and/or PC6 regulate the processing of endogenously derived MT1-MMP. …”

Section: Proprotein Convertase-dependent Processing Of Mt1-mmp In Ht-mentioning

confidence: 90%

“…␣ 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). To determine if these ␣ 1 PDX-sensitive convertases participate in MT1-MMP maturation, processing was examined in COS-1 cells cotransfected with MT1-MMP.…”

Section: ␣ 1 Pdx Blocks Promt1-mmp Processingmentioning

confidence: 99%

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

Yana

Weiss

2000

MBoC

278

270

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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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BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development

Cited by 215 publications

References 48 publications

Xenopus Lefty requires proprotein cleavage but not N‐linked glycosylation to inhibit nodal signaling

Xenopus Lefty requires proprotein cleavage but not N‐linked glycosylation to inhibit nodal signaling

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

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

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