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 ␤ (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., 1997; Massague ´, 1998; Whitman, 1998), transcriptional globular domain (Greenwald et al., 1999; Kirsch et al., 2000b) and the cytoplasmic region by a short juxtamem-control (Derynck et al., 1998; Massague ´and Wotton, 2000), and the regulation of these processes (Massague ´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 (Massague ´, 1998, and ref-family, 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 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 Massague ´, 1998). Four are present in Caenorhabditis Smad proteins are the only known TGF␤ 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 domain...

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). This data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression.

Although p27Kip1 has been considered a general inhibitor of G 1 and S phase cyclin-dependent kinases, we report that the interaction of p27 with two such kinases, cyclin A-Cdk2 and cyclin D-Cdk4, is different. In Mv1Lu cells containing a p27 inducible system, a 6-fold increase over the basal p27 level completely inhibited Cdk2 and cell cycle progression. In contrast, the same or a larger increase in p27 levels did not inhibit Cdk4 or its homologue Cdk6, despite extensive binding to these kinases. A p27-cyclin A-Cdk2 complex formed in vitro was essentially inactive, whereas a p27-cyclin D2-Cdk4 complex was active as a retinoblastoma kinase and served as a substrate for the Cdk-activating kinase Cak. High concentrations of p27 inhibited cyclin D2-Cdk4, apparently by conversion of active complexes into inactive ones by the binding of additional p27 molecules. In contrast to their differential interaction, cyclin A-Cdk2 and cyclin D2-Cdk4 were similarly inhibited by bound p21Cip1/Waf1