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Fig. 3. A model for TGFß1 signal transduction during mouse angiogenesis.
TGFß1 can activate two type I receptors in cultured endothelial cells
(reviewed by Byfield and Roberts,
2004). As expected, it activates Alk5 (also called TßRI), the
canonical TGFß type 1 receptor, and surprisingly also Alk1, an orphan
type 1 receptor that stimulates Smad1 phosphorylation, which is normally
associated with BMP signaling (see Table
1). Different levels of TGFß promote different endothelial
cell responses, supporting a model in which low signaling activity promotes
activation responses and high signaling activity promotes resolution
responses. The specific phase of angiogenesis regulated by Alk1 is
controversial (`?'). The cell-surface protein endoglin reportedly stimulates
Alk1 signaling and antagonizes Alk5 signaling
(Lebrin et al., 2004;
Pece-Barbara et al., 2005)
through unclear mechanisms. Tak1 knockout mice have embryonic
vasculature defects, suggesting that this non-Smad pathway is involved in
TGFß signaling during angiogenesis. [For comprehensive discussions of
this model, see Marchuk (Marchuk, 2003) and Lebrin et al.
(Lebrin et al., 2005).] Alk,
activin receptor-like kinase; P, phosphate; Tak1, TGFß activated kinase
1; Txn Fac, transcription factor.
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