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First published online September 9, 2005
doi: 10.1242/10.1242/dev.02023

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TGFß signaling at the summit

¹ Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA
² Cutaneous Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129, USA

View larger version (34K): [in a new window]   Fig. 1. A schematic overview of TGFß signal transduction. Numbers in circles refer to specific examples given in Table 1. Abbreviations: BMP, bone morphogenetic protein; coA, co-activator; coR, co-repressor; I-Smad, inhibitory Smad; P, phosphate; Pks, protein kinases; R-Smad, receptor-regulated Smad; Txn Fac, transcription factor; Ub ligase, ubiquitin ligase. Black and green lines indicate positive interactions, red lines indicate inhibitory ones.

View larger version (26K): [in a new window]   Fig. 2. Extracellular regulation of TGFß ligand family activity. Ligand activity can be masked in latent complexes and activated by the action of extracellular metalloproteases in the BMP1/Tolloid family (Massague, 1998; Dale, 2000; Ashe, 2005). Activity can be modulated both positively and negatively by cell surface proteins, as discussed in the text. This figure provides a snapshot of systems discussed at the meeting, and is not intended to be a comprehensive review. Abbreviations: Sog, Short gastrulation, Tsg, Twisted gastrulation

View larger version (31K): [in a new window]   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.