GDF11 Forms a Bone Morphogenetic Protein 1-Activated Latent Complex That Can Modulate Nerve Growth Factor-Induced Differentiation of PC12 Cells

Ge, Gaoxiang; Hopkins, Delana R.; Ho, Wen‐Bin; Greenspan, Daniel S.

doi:10.1128/mcb.25.14.5846-5858.2005

Cited by 137 publications

(154 citation statements)

References 45 publications

(91 reference statements)

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“…Although such cleavage is sufficient for activating most TGFβ-like proteins (Hogan, 1996), prototypical family members TGFβ 1-3 remain noncovalently bound to their cleaved prodomains in latent complexes (Massague, 1998). More recently it has been demonstrated that GDF8 and 11, which share ~90% sequence identity in their mature regions (Gamer et al, 1999;Ge et al, 2005;Nakashima et al, 1999), are also noncovalently bound to their respective prodomains in latent complexes (Ge et al, 2005;Hill et al, 2002;Lee and McPherron, 2001;Wolfman et al, 2003) (Fig. 5B).…”

Section: Growth and Differentiation Factors 8 And 11 (Gdfs 8 And 11)mentioning

confidence: 99%

“…GDF11 also appears to play roles in anterior-posterior patterning of the axial skeleton (McPherron et al, 1999). BMP1/TLD-like proteinases have been demonstrated to cleave within GDF8 and 11 prodomain sequences, thus liberating the mature proteins and enabling downstream signal transduction (Ge et al, 2005;Wolfman et al, 2003). Interestingly, recombinant GDF8 prodomain with a single amino acid substitution that renders it resistant to cleavage by BMP1/TLD-like proteinases is capable of inducing increased muscle mass when injected into normal adult mice, whereas wild type GDF8 prodomain has no effect (Wolfman et al, 2003).…”

Section: Growth and Differentiation Factors 8 And 11 (Gdfs 8 And 11)mentioning

confidence: 99%

“…In addition to previously known roles of the BMP1/TLD-like proteinases in ECM formation and patterning, new roles are beginning to emerge. Among these are the roles that these proteinases appear to play in formation of neural tissues (Liu et al, 1997;Ge et al, 2005;Meyer and Aberle, 2006;Maertens et al, 2007). To further understand the varied roles of the BMP1/TLD-like proteinases will require a further cataloguing of their substrates, which may require high-throughput approaches, such as mass-spectrometric analyses of protein cleavage products produced by wild type cells, but not by cells null for individual, or combinations of BMP1/TLD-like proteinases.…”

Section: Perspectivesmentioning

confidence: 99%

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The bone morphogenetic protein 1/Tolloid-like metalloproteinases

2007

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A decade ago, bone morphogenetic protein 1 (BMP1) was shown to provide the activity necessary for proteolytic removal of the C-propeptides of procollagens I-III: precursors of the major fibrillar collagens. Subsequent studies have shown BMP1 to be the prototype of a small group of extracellular metalloproteinases that play manifold roles in regulating formation of the extracellular matrix (ECM). Soon after initial cloning of BMP1, genetic studies showed the related Drosophila proteinase Tolloid (TLD) to be necessary for formation of the dorsal-ventral axis in early embryogenesis. It is now clear that the BMP1/TLD-like proteinases, conserved in species ranging from Drosophila to humans, act in dorsal-ventral patterning via activation of transforming growth factor β (TGFβ)-like proteins BMP2, BMP4 (vertebrates) and decapentaplegic (arthropods). More recently, it has become apparent that the BMP1/TLD-like proteinases are key activators of a broader subset of the TGFβ superfamily of proteins, with implications that these proteinases may be key in orchestrating formation of ECM with growth factor activation and BMP signaling in morphogenetic processes.

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Section: Growth and Differentiation Factors 8 And 11 (Gdfs 8 And 11)mentioning

confidence: 99%

Section: Growth and Differentiation Factors 8 And 11 (Gdfs 8 And 11)mentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

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The bone morphogenetic protein 1/Tolloid-like metalloproteinases

2007

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“…8 BMP-1 may convert precursor proteins, including laminin-5, procollagen, growth and differentiation factors 8 and 11, and TGF-b1, into their active forms, which play manifold roles in cell adhesion and in regulating mineralization in the extracellular matrix of hard tissue. 8,[10][11][12][13][14][15][16][17] BMP-1 may also activate two other BMP family members, BMP-2 and BMP-4, by cleaving their antagonist, chordin. 11 Therefore, BMP-1 is believed to be an intermediate factor between the TGF-b and BMP signaling pathways.…”

mentioning

confidence: 99%

Survival impact of psammoma body, stromal calcification, and bone formation in papillary thyroid carcinoma

et al. 2009

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The presence of calcification is the most significant ultrasonographic finding in evaluating thyroid nodules. Calcifications are more frequently detected in papillary thyroid carcinoma than in other thyroid lesions. However, the clinical significance of calcification, including clinical correlations and impact on survival, and the molecular mechanism responsible for calcification in papillary thyroid carcinoma remain uncertain. We performed a retrospective study of patients with primary common-type papillary thyroid carcinoma to determine the clinical correlations of calcification and its impact on survival. Histologically, calcification was classified as either psammoma bodies, stromal calcification, or bone formation. They were identified in 25, 47, and 13% of all 229 cases of papillary thyroid carcinoma, respectively. The presence of psammoma bodies was significantly correlated with gross lymph node metastasis and stage grouping. Both stromal calcification and bone formation were significantly correlated with patient age. In addition, stromal calcification was associated with pT classification and gross lymph node metastasis. Papillary thyroid carcinoma with, compared to that without, psammoma bodies was associated with poorer disease-free survival. We examined the quantitative expression of BMP-1, a metalloproteinase that is reported to be involved in bone and extracellular matrix formations, and found that its expression was significantly higher in tumors with psammoma bodies or with stromal calcification (P ¼ 0.0464 and 0.0272, respectively). These results suggest that the presence of psammoma bodies is a useful predictor of outcome for patients suffering from papillary thyroid carcinoma.

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“…Mouse Gdf11 (21) and HA epitope-tagged human LTBP-2 and mouse LTBP-3 (13) were expressed using pcDNA3 vectors.…”

Section: Methodsmentioning

confidence: 99%

Latent Transforming Growth Factor β-Binding Proteins-2 and -3 Inhibit the Proprotein Convertase 5/6A

Sun

Essalmani

Susan‐Resiga

et al. 2011

Journal of Biological Chemistry

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The basic amino acid-specific proprotein convertase 5/6 (PC5/6) is an essential secretory protease, as knock-out mice die at birth and exhibit multiple homeotic transformation defects, including impaired bone morphogenesis and lung structure. Some of the observed defects were attributed to impaired processing of the TGF␤-like growth differentiating factor 11 precursor (proGdf11). In this work we present evidence that the latent TGF␤-binding proteins 2 and 3 (LTBP-2 and -3) inhibit the extracellular processing of proGdf11 by PC5/6A. This is partly due to the binding of LTBPs in the endoplasmic reticulum to the zymogen proPC5/6A, thus allowing the complex to exit the endoplasmic reticulum and be sequestered as an inactive zymogen in the extracellular matrix but not at the cell surface. This results in lower levels of PC5/6A in the media, without affecting those of PACE4, Furin, or a soluble form of PC7. The secreted soluble protease-specific activity of PC5/6A or a variant lacking the C-terminal Cys-rich domain (PC5/6-⌬CRD) is significantly decreased when co-expressed with LTBPs in cells. A similar enzymatic inhibition seems to apply to PACE4 and Furin. In situ hybridization analyses revealed extensive co-localization of PC5/6 and LTBP-3 mRNAs in mice at embryonic day 15.5 and post partum day 1. In conclusion, this is the first time that a zymogen of the proprotein convertases was shown to exit the endoplasmic reticulum in the presence of LTBPs, representing a potential novel mechanism for the regulation of PC5/6A activity, e.g. in tissues such as bone and lung where LTBP-3 and PC5/6 co-localize. The mammalian proprotein convertases (PCs)2 form a family of nine serine proteinases related to subtilisin that primarily modify the activation state of a wide range of bioactive proteins. Seven PCs, PC1 (also known as PC3), PC2, Furin, PC4, PC5/6 (also known as PC5 or PC6), PACE4, and PC7, cleave protein precursors at basic sites during their transit through the secretory pathway and/or at the cell surface. Among these basic amino acid-specific PCs, Furin, PC5/6, PACE4, and PC7 are ubiquitous or are widely distributed, although they exhibit characteristic patterns of expression in specific tissues and cells.PC5/6 is the only member of the PC family that exists as two isoforms: soluble PC5/6A (1) and membrane-bound PC5/6B, which has an extended C-terminal Cys-rich domain (CRD) (2). Except in the small intestine and kidney, PC5/6A is the major isoform in all other tissues (3). PC5/6A is synthesized as an inactive zymogen (proPC5/6A). It undergoes a first autocatalytic processing in the endoplasmic reticulum (ER) at RTKR 116 2 (supplemental Fig. S1), resulting in a tight binding complex of the inhibitory prosegment with the protease, allowing the protein to exit the ER. It is then activated by a second autocatalytic cleavage within the prosegment at RTIKR 84 2 (supplemental Fig. S1), which mostly occurs on the cell surface, where PC5/6A is anchored through its CRD that binds to heparan sulfate proteoglycans (HSPGs) (4).PC5/...

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GDF11 Forms a Bone Morphogenetic Protein 1-Activated Latent Complex That Can Modulate Nerve Growth Factor-Induced Differentiation of PC12 Cells

Cited by 137 publications

References 45 publications

The bone morphogenetic protein 1/Tolloid-like metalloproteinases

The bone morphogenetic protein 1/Tolloid-like metalloproteinases

Survival impact of psammoma body, stromal calcification, and bone formation in papillary thyroid carcinoma

Latent Transforming Growth Factor β-Binding Proteins-2 and -3 Inhibit the Proprotein Convertase 5/6A

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