TGF b Signaling in Growth Control

receptors funnel their activities through one of two groups of Smad proteins (Figure 1). Several key events in the TGFb receptor activation Joan Massagué,* Stacy W. Blain, and Roger S. Lo Cell Biology Program Howard Hughes Medical Institute Memorial Sloan-Kettering Cancer Center process are now understood. Adjacent to the kinase domain of the type I receptors is a conserved 30 amino New York, New York 10021 acid segment known as the GS region (for a GSGS sequence it contains). In the basal state, the GS region The transforming growth factor b (TGFb) pathway occuforms a wedge that presses against the catalytic center (Huse et al., 1999). The immunophilins FKBP12 and pies a central position in the signaling networks that control the growth, differentiation, and final fate of metaFKBP12.6 bind to the GS domain and stabilize this inactive conformation. Activation occurs when the type II zoan cells. Over the past few years, remarkable progress has been made in identifying the central components receptors phosphorylate the GS domain. To achieve this, the ligand must bring together type I and type II of this pathway, defining their interactions, and deciphering how a cell interprets its signals. Along the way, receptors, forming a heteromeric complex. The ligands themselves are dimers (most often homodimers held genetic alterations have been discovered in this pathway that provide answers to long-standing questions together by disulfide bonds), and each monomer has contact sites for type I and type II receptors, as defined about the molecular basis of certain common somatic disorders as well as rare inherited ones. Recent reviews using BMP2 (Kirsch et al., 2000a). The extracellular region of the receptors is formed by a small, tightly folded have covered TGFb signal transduction (Heldin et al., 1997; Massagué, 1998; Whitman, 1998), transcriptional globular domain (Greenwald et al., 1999; Kirsch et al., 2000b) and the cytoplasmic region by a short juxtamemcontrol (Derynck et al., 1998; Massagué and Wotton, 2000), and the regulation of these processes (Massagué brane segment, a protein kinase domain, and often little else (Huse et al., 1999). In several cases, the extracellular and Chen, 2000). The present review focuses on the control of cell growth and differentiation by the TGFb or cytoplasmic regions contain alternatively spliced extensions of unknown function (Massagué, 1998, and reffamily, and the human disorders that result from genetic alterations in these pathways. erences therein). One of these extensions, on the carboxy-terminus of the BMP type II receptor BMPR-II, is the target of mutations that cause familial primary The Basics of TGFb Signaling Nearly thirty members of the TGFb family have been pulmonary hypertension in humans (see below). described in human, and many orthologs are known in mouse, Xenopus, and other vertebrates (Hogan, 1996; Smad Transcription Factors Massagué, 1998). Four are present in Caenorhabditis Smad proteins are the only known TGFb receptor subelegans (Padgett et al., 1998), and seven in Drosophila strates capable of signal transduction. They consist of melanogaster (Raftery and Sutherland, 1999). The family two conserved globular domains known as the MH1 is divided into two general branches (the BMP/GDF and (Mad homology 1) and MH2 domains coupled by a linker TGFb/Activin/Nodal branches) whose members have diregion (Figure 3) (Shi et al., 1997, 1998). The MH1 domain verse, albeit often complementary, effects. Additional recognizes the DNA sequence CAGAC (Kim et al., 1997; members such as inhibin-a act as ligand antagonists. Shi et al., 1998; Zawel et al., 1998) whereas the MH2 Some family members are expressed only in a few cell domain binds the transcriptional coactivators p300 and types or for limited periods of time during development, CBP in competition with the corepressors TGIF, Ski, and whereas others are widespread during embryogenesis SnoN (reviewed in Massagué and Wotton, 2000). and in adult tissues. AMH/MIS (Anti-Müllerian hormone Smads 2 and 3 (and perhaps the other Smads as well) or Müllerian inhibiting substance) and GDF8/myostatin have intrinsic nuclear import activity in the MH2 domain are examples of the former; TGFb1 and BMP4 of the (Xu et al., 2000a). In the cell, however, most Smads are latter. kept in the cytoplasm in the basal state, which ensures TGFb factors initiate signaling by assembling receptor their prompt exposure to activated receptors. Cytocomplexes that activate Smad transcription factors (Figplasmic retention of Smads 2 and 3 is achieved in part by ure 1) (Massagué, 1998). The ligand brings together binding to the protein SARA (Smad anchor for receptor members from two families of receptor serine/theonine activation) (Tsukazaki et al., 1998). SARA plays three kinases, known as the type I and type II receptors. The roles: it tethers Smads in the cytoplasm, it occludes a only known function of the type II receptors is to activate nuclear import signal on the MH2 domain (Xu et al., the type I receptors. The type I receptors propagate the 2000a), and it facilitates Smad presentation to the actisignal by phosphorylating the Smads (Figure 1). Each vated receptors (Tsukazaki et al., 1998). Besides the ligand may have a choice of several type I and/or type Smad binding region, SARA contains a FYVE domain, II receptors (Figure 2), and a given cell may express a structure that in other proteins mediates binding to different receptor forms. However, the various type I phosphatidylinositol 3-phosphate on endosome membranes. The Smads that serve as receptor substrates * To whom correspondence should be addressed (e-mail: j-massague@ski.mskcc.org). (R-Smads) fall into two groups, each serving one branch brought to you by CORE View metadata, citation and similar papers at core.ac. uk