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E-selectin ligand–1 regulates growth plate homeostasis in mice by inhibiting the intracellular processing and secretion of mature TGF-β
Tao Yang, … , Arthur L. Beaudet, Brendan Lee
Tao Yang, … , Arthur L. Beaudet, Brendan Lee
Published June 7, 2010
Citation Information: J Clin Invest. 2010;120(7):2474-2485. https://doi.org/10.1172/JCI42150.
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Research Article Bone biology

E-selectin ligand–1 regulates growth plate homeostasis in mice by inhibiting the intracellular processing and secretion of mature TGF-β

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Abstract

The majority of human skeletal dysplasias are caused by dysregulation of growth plate homeostasis. As TGF-β signaling is a critical determinant of growth plate homeostasis, skeletal dysplasias are often associated with dysregulation of this pathway. The context-dependent action of TFG-β signaling is tightly controlled by numerous mechanisms at the extracellular level and downstream of ligand-receptor interactions. However, TGF-β is synthesized as an inactive precursor that is cleaved to become mature in the Golgi apparatus, and the regulation of this posttranslational intracellular processing and trafficking is much less defined. Here, we report that a cysteine-rich protein, E-selectin ligand–1 (ESL-1), acts as a negative regulator of TGF-β production by binding TGF-β precursors in the Golgi apparatus in a cell-autonomous fashion, inhibiting their maturation. Furthermore, ESL-1 inhibited the processing of proTGF-β by a furin-like protease, leading to reduced secretion of mature TGF-β by primary mouse chondrocytes and HEK293 cells. In vivo loss of Esl1 in mice led to increased TGF-β/SMAD signaling in the growth plate that was associated with reduced chondrocyte proliferation and delayed terminal differentiation. Gain-of-function and rescue studies of the Xenopus ESL-1 ortholog in the context of early embryogenesis showed that this regulation of TGF-β/Nodal signaling was evolutionarily conserved. This study identifies what we believe to be a novel intracellular mechanism for regulating TGF-β during skeletal development and homeostasis.

Authors

Tao Yang, Roberto Mendoza-Londono, Huifang Lu, Jianning Tao, Kaiyi Li, Bettina Keller, Ming Ming Jiang, Rina Shah, Yuqing Chen, Terry K. Bertin, Feyza Engin, Branka Dabovic, Daniel B. Rifkin, John Hicks, Milan Jamrich, Arthur L. Beaudet, Brendan Lee

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Figure 6

ESL-1 can directly bind to TGF-β and inhibits TGF-β signaling.

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ESL-1 can directly bind to TGF-β and inhibits TGF-β signaling.
(A) ESL-1...
(A) ESL-1 coimmunoprecipitates with both the proTGF-βs and TGF-β ligands. Transfection scheme is shown at the top. Note that anti-V5 antibody detects the V5-tagged proTGF-β1, proTGF-β2 (~50 kDa), and mature TGF-β peptides (TGF-β1: 15 kDa and TGF-β2: 12 kDa). The top 4 panels show Western blots of input lysates, and the bottom 3 show Western blot (WB) for immunoprecipitation. Antibodies used are listed on the left. ProTGF-β1 and proTGF-β2 and their mature ligands are all immunoprecipitated with Myc antibody, and vice versa, suggesting direct interaction between TGF-β and ESL-1. (B) ESL-1 cannot bind mature TGF-β without LAP. rhTGF-β1 (100 ng) was added to lysates of COS7 cells expressing ESL-1-Myc and then coimmunoprecipitated with anti-Myc antibody. The precipitates were analyzed with reducing Western blots. rhTGF-β1 (15 ng) was used as loading control (asterisk). (C) ESL-1 can effectively inhibit TGF-β activity from the plasmid-produced proTGF-β1 but cannot inhibit signaling from the exogenously added rhTGF-β1 (n = 3; **P < 0.01).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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