9 TGF-β Signaling from Receptors to Smads

Abstract

Binding of transforming growth factor-β (TGF-β) family members to their heteromeric complexes of type I and type II serine-threonine kinase receptors makes it possible for the type II receptor to phosphorylate and activate the type I receptor (see Chapter 6). Although several substrates for the type I receptor kinases have been identified, the most important ones for the transmission of the intracellular signals are members of the Smad family of signal transducers. The receptor-activated (R-) Smads (Smad1, Smad5, and Smad8, for bone morphogenic proteins [BMPs] and Smad2 and 3 for TGF-βs and activins) are phosphorylated by the type I receptors and then form hetero-oligomeric complexes with the common mediator (co-) Smad (only one co-Smad in humans, Smad4), which are translocated to the nucleus where they regulate the transcription of specific genes. The third Smad subfamily is represented by the inhibitory (I-) Smads, that is, Smad6 and Smad7, which, on the one hand, inhibit signaling via heteromeric serine-threonine kinase receptor complexes in a feedback mechanism and, on the other hand, promote certain non-Smad signaling pathways. The inhibitory Smads are discussed in Chapter 12 and are not covered in this chapter. The aim of this chapter is to review the mechanism whereby Smads are activated by receptors, how they are translocated to the nucleus, and how their activities are modulated by posttranslational modifications. The role of Smad complexes as transcriptional regulators in the nucleus is not discussed here (see Chapter 10). THE SMAD FAMILY Discovery of the Smads The Smad family was...