Phosphorylation of Smad signaling proteins by receptor serine/threonine kinases.

Abstract

Transforming growth factor-β (TGF-β) family members, which include TGF-βs, activins, and bone morphogenetic proteins (BMPs), elicit their multifunctional effects by binding to and complex formation of type I and type II serine/threonine kinase receptors (see Fig. 1). Each family member signals via distinct combinations of type I and type II receptors, both of which are required for signaling. Upon formation of the heteromeric receptor complex, the type I receptor is phosphorylated by the type II receptor kinase. Phosphorylation occurs predominantly in a region rich in glycine and serine residues (GS domain) in the juxtamembrane domain of the type I receptor, which possibly leads to a conformational change and thereby activates the type I receptor kinase (see Fig. 1) (, , ). The activated type I receptor propagates the signal downstream through transient interaction with, and phosphorylation of, particular Smoeand mad related protein (Smad) molecules (, , ). Certain Smads are phosphorylated directly by activated type I receptors in a differential manner; they are therefore termed pathway-restricted Smads. Whereas Smad2 and Smad3 act in TGF-β and activin pathways, Smad1, Smad5, and Smad8 are thought to act in BMP pathways. Phosphorylation occurs at the two most C-terminal serine residues in a conserved C-terminal Ser-Ser-X-Ser motif (see Fig. 2). Pathway-restricted Smads oligomerize with Smad4, which acts as a common mediator in TGF-β, activin, and BMP signaling. After translocation to the nucleus, the oligomers interact with DNA directly, or in complex with other DNA-binding proteins, and control transcription of target genes (see Figs. 1 and 2). Recently, inhibitory Smads, Smad6, and Smad7, have been identified that antagonize TGF-β family signaling (). Open image in new window Fig. 1. TGF-β signaling through Smad proteins. A hypothetical signal transduction pathway for TGF-β family members through their serine/threonine kinase receptors and downstream effector molecules of the Smad family, is depicted. Open image in new window Fig. 2. Functional domains in Smad proteins. Type I receptor-induced phosphorylation of pathway-restricted Smads may induce an unfolding of the N-and C-terminal domains (shown on left side), allowing heteromeric complex formation and transcriptional activation mediated by C-terminal domain and direct DNA-binding via N-terminal domain (shown on right side). The phospho-acceptor site of type I receptor kinase is indicated. The conserved regions in the N-terminal domain (MH1 domain) and C-terminal domain (MH2 domain), are indicated by black and hatched boxes, respectively.