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.