Tie2-R849W mutant in venous malformations chronically activates a functional STAT1 to modulate gene expression.
J Invest Dermatol
; 128(9): 2325-33, 2008 Sep.
Article
en En
| MEDLINE
| ID: mdl-18401423
ABSTRACT
Tie2 is an endothelial receptor tyrosine kinase. An amino-acid substitution of tryptophan for arginine at residue 849 (Tie2-R849W) leads to a ligand-independent activation of its kinase activity. This mutation has been associated with familial venous malformations (VMs), manifested by variable thickness or lack of smooth-muscle cells in the veins of patient lesions. The underlying mechanism for Tie2-R849W action in endothelial cells remains elusive. In this study, we used adenoviral infection to differentiate the effects of ectopic Tie2 (wild type, kinase-dead K855A, or constitutively active R849W) expression on endothelial cellular behaviors and Tie2-mediated downstream targets. Ectopic Tie2 reduced endothelial cell proliferation and serum withdrawal-induced apoptosis, while stimulating migration. When comparing R849W with K855A and its wild-type counterpart, a functional tyrosine kinase activity was required only for migration, and constitutively active Tie2-R849W conferred highest resistance to serum-induced apoptosis, but lowest ability to maintain tube-like structures formed on Matrigel. We further demonstrated that Tie2-R849W chronically induced STAT1 tyrosine phosphorylation and the promoter activity of STAT1-responsive IFN-regulatory factor 1 (IRF1). Although STAT1 phosphorylation required JNK and p38MAPK activation, only JNK activation was essential for IRF1 promoter activation by Tie2-R849W. Additional studies are needed to study the role of STAT1 activation in VMs.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_cardiovascular_diseases
/
6_congenital_chromosomal_anomalies
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6_other_respiratory_diseases
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6_trachea_bronchus_lung_cancer
Asunto principal:
Venas
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Receptor TIE-2
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Factor de Transcripción STAT1
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Malformaciones Vasculares
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Mutación
Límite:
Female
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Humans
Idioma:
En
Revista:
J Invest Dermatol
Año:
2008
Tipo del documento:
Article