Altered TGF-ß endocytic trafficking contributes to the increased signaling in Marfan syndrome.
Biochim Biophys Acta Mol Basis Dis
; 1864(2): 554-562, 2018 Feb.
Article
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| MEDLINE
| ID: mdl-29174139
ABSTRACT
The main cardiovascular alteration in Marfan syndrome (MFS) is the formation of aortic aneurysms in which augmented TGF-ß signaling is reported. However, the primary role of TGF-ß signaling as a molecular link between the genetic mutation of fibrillin-1 and disease onset is controversial. The compartmentalization of TGF-ß endocytic trafficking has been shown to determine a signaling response in which clathrin-dependent internalization leads to TGF-ß signal propagation, and caveolin-1 (CAV-1) associated internalization leads to signal abrogation. We here studied the contribution of endocytic trafficking compartmentalization to increased TGF-ß signaling in vascular smooth muscle cells (VSMC) from MFS patients. We examined molecular components involved in clathrin- (SARA, SMAD2) and caveolin-1- (SMAD7, SMURF2) dependent endocytosis. Marfan VSMC showed higher recruitment of SARA and SMAD2 to membranes and their increased interaction with TGF-ß receptor II, as well as higher colocalization of SARA with the early endosome marker EEA1. We assessed TGF-ß internalization using a biotinylated ligand (b-TGF-ß), which colocalized equally with either EEA1 or CAV-1 in VSMC from Marfan patients and controls. However, in Marfan cells, colocalization of b-TGF-ß with SARA and EEA1 was increased and accompanied by decreased colocalization with CAV-1 at EEA1-positive endosomes. Moreover, Marfan VSMC showed higher transcriptional levels and membrane enrichment of RAB5. Our results indicate that increased RAB5-associated SARA localization to early endosomes facilitates its TGF-ß receptor binding and phosphorylation of signaling mediator SMAD2 in Marfan VSMC. This is accompanied by a reduction of TGF-ß sorting into multifunctional vesicles containing cargo from both internalization pathways.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
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Miocitos del Músculo Liso
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Endocitosis
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Factor de Crecimiento Transformador beta1
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Síndrome de Marfan
Límite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Biochim Biophys Acta Mol Basis Dis
Año:
2018
Tipo del documento:
Article
País de afiliación:
España