TGFβ Signaling in Growth Control, Cancer, and Heritable Disorders

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 ␤ (TGF␤) pathway occu-forms 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 meta-FKBP12.6 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 TGF␤ signal transduction (Heldin et al., 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 TGF␤ or cytoplasmic regions contain alternatively spliced extensions of unknown function (Massagué , 1998, and ref-family, and the human disorders that result from genetic alterations in these pathways. erences therein). One of these extensions, on the car-boxy-terminus of the BMP type II receptor BMPR-II, is the target of mutations that cause familial primary The Basics of TGF␤ Signaling Nearly thirty members of the TGF␤ 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 TGF␤ receptor sub-elegans (Padgett et al., …