6 Signaling Receptors of the TGF-β Family

Transforming growth factor-β (TGF-β) is the prototypical member of a family of structurally related cytokines that function as secreted morphogens to control cell fate throughout development and during homeostasis. TGF-β-related molecules are expressed in all metazoan organisms investigated to date and include TGF-βs, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins, inhibins, Mullerian inhibiting substance (MIS, also termed anti-Mullerian hormone, AMH), nodal, and leftys (de Caestecker 2004). In multicellular organisms, extracellular cues are critical to allow the specialization of cell function and the establishment of complex tissues. Transmembrane signaling receptors are the primary conduit whereby extracellular polypeptide cues regulate cell function. Broad classes of signaling receptors have been defined for a range of extracellular factors, including multipass transmembrane receptors, such as G-protein-coupled receptors; Frizzleds, which transduce Wnt signals; and Smoothened and Patched, which regulate Hedgehog signals. A broad range of structurally diverse receptors with single transmembrane regions have also been defined. Their intracellular regions can harbor catalytic domains, such as the receptor tyrosine kinases (RTKs), or can serve as scaffolds that mediate the assembly of large, multicomponent signaling complexes, usually in response to ligand-induced receptor clustering. Finally, coreceptors can promote binding of extracellular factors to their appropriate signaling receptors and thus have a critical role in mediating high-affinity and high-specificity interactions. For example, the glycosaminoglycan heparin sulfate, which is found in the extracellular environment, is required for fibroblast growth factor (FGF) binding to its cognate RTK signaling receptors. Coreceptors can also be tethered to the membrane via glycosylphosphatidylinositol...