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The type I TGFβ receptor ALK‐1 functions in TGFβ‐mediated signaling in angiogenesis
Author(s) -
DUFFY IAIN,
Watters January,
HAWKER JAMES
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.525.3
Subject(s) - angiogenesis , endoglin , cancer research , activin receptor , smad , microbiology and biotechnology , transforming growth factor , signal transduction , activin type 2 receptors , r smad , fibroblast growth factor , vascular endothelial growth inhibitor , chemistry , biology , receptor , vascular endothelial growth factor a , vascular endothelial growth factor , tgf beta signaling pathway , stem cell , biochemistry , cd34 , vegf receptors
Activin‐Like Kinase 1 (ALK1, TSR1), a type I transforming growth factor (TGFβ) family receptor found in endothelial cells, is involved in angiogenesis (new blood vessel formation). Control of angiogenesis is critical in diseases such as cancer, heart disease, or wound repair. We show that expression of ALK‐1 but not ALK 5 type I receptor increases dramatically in endothelial cells after tube formation stimulated by TGFβ + fibroblast growth factor (FGF). FGF‐2 + TGFβ also upregulate ALK 1 and downregulate ALK5 cell surface expression in human endothelial cells. Further, we show that TGFβ signals through a complex of ALK 1, the ALK signaling protein Smad 1, and the co‐receptor endoglin. Three ligands, TGFβ, activin, and bone morphogenetic protein 9 (BMP‐9), have been shown to bind ALK‐1. We show that endogenous activin binds ALK 1 and can be displaced by exogenous TGFβ. This suggests it may function to regulate control of ALK 1 activation. Antisense RNA that targets ALK 1 and also ALK 5 disrupts tube formation. This data suggests a critical role for the ALK‐1 receptor in endothelial tube formation. We are generating inactive mutants of ALK‐1, ALK‐5, and endoglin to further test their roles in angiogenesis and signal transduction. We hope to dissect the role of ALK‐1 and TGFβ family ligands in angiogenesis of tumors. Research support was from AHA‐TX and Dept Veteran's Affairs grants (JH) and funds from Saint Leo University (ID).