Ventral specification of mesoderm and ectoderm depends on signaling by members of the bone morphogenetic protein (Bmp) family. Bmp signals are transmitted by a complex of type I and type II serine/threonine kinase

During establishment of the body plan, signaling events regulate cellular behavior and specification. Members of the transforming growth factor β (Tgfβ) superfamily of signaling molecules have been shown to be crucial mediators of a variety of such processes (reviewed by Massagué, 1998). In target cells, Tgfβ signaling is transduced by transmembrane receptors of the serine/threonine kinase family, which themselves regulate the activity of members of the family of Smad transcription factors. Two types of receptors can be distinguished, type I and type II, which form heteromeric complexes upon ligand binding. Ligand binding occurs either in a sequential or a cooperative manner. The sequential mode, as characteristic for Tgfβ and activin receptors, involves direct binding of the ligand to high-affinity type II receptors and subsequent recruitment of type I receptors to the complex, whereas ligands bound in a cooperative mode, such as the bone morphogenetic proteins Bmp2, Bmp4 and Bmp7 or the growth differentiation factor Gdf5, display low affinity to both type I and type II receptors alone, but high affinity to the two receptors together (reviewed in Massagué, 1998). The type II receptors have constitutive kinase activity, leading to phosphorylation and activation of the type I receptor after ligand-induced complex formation. Activated type I receptors themselves phosphorylate and activate Smad proteins, which thereafter enter the nucleus to regulate transcription of target genes. In line with their distinct functions, type I and type II receptors differ in several structural features. Both have a relatively short (approx. 150 amino acids) extracellular domain that contains 10 or more cysteines to determine the general folding of this region. Three of these cys-residues near the transmembrane domain constitute a specific cluster, the cysteine box, which is conserved in all serine/threonine transmembrane kinase receptors (Wrana et al., 1994). A unique feature of type I receptors is the GS domain, which precedes the kinase domain in the cytoplasmic part of the receptors. The GS domain contains several serine residues that can be phosphorylated by the type II receptors during signal transduction and type I receptor activation. Another special region of type I receptors is the L45 loop, a stretch of 10 amino acids of the kinase domain that determines the specificity of the receptors to the various receptor-regulated Smad proteins (Chen et al., 1998a; Chen et al., 1998b). The sequence of this L45 loop is highly divergent between different subgroups of 849 Development 128, 849-858 (2001) Printed in Great Britain © The Company of Biologists Limited 2001 DEV3293