NO to small mothers against decapentaplegic (Smad).

Transforming Growth Factor(TGF) is the prototype of a superfamily of multifunctional proteins which includes activins and bone morphogenetic proteins (BMPs). TGFis involved in the regulation of diverse cellular processes such as cell proliferation, differentiation, apoptosis and migration, as well as moderating cell–cell and cell–matrix interactions. It plays a pivotal role in embryonic development, and perturbations of TGFsignaling may have profound pathological consequences in a wide variety of diseases. (For general reviews on TGFactions, please see Massagué1 and Kim et al.2) Cellular responses to TGFare complex and, depending on cell type and conditions, it can induce stimulatory or inhibitory effects. In the heart, TGFstimulates hypertrophy of cardiomyocytes and proliferation of fibroblasts, contributing to myocardial fibrosis and dysfunction.3 In the blood vessel wall, TGFinhibits proliferation and migration of vascular smooth muscle cells, and defective signaling can lead to pathological vascular remodeling.4 TGFis also a potent suppressor of leukocyte activation, and under some conditions can exert a protective immunomodulatory role in atherosclerosis.5,6 TGFcan act as an inhibitor or a stimulator of endothelial proliferation, impacting on different stages of angiogenesis.7,8 Despite the diversity in actions, a recurring theme for TGFin the cardiovascular system is the stimulation of increased matrix production and tissue remodeling. Amplification of the TGFresponse is also commonly observed, attributable to autoinduction of the TGFgene.9 Because TGFis involved in such a vast diversity of regulation of cellular events, it is therefore not surprising that its signaling is characterized by a remarkable degree of complexity and subtlety. Members of the TGFsuperfamily interact with 2 classes of serine/threonine receptors. TGFbinds avidly to its type II receptor (T R-II), and the receptor– ligand complex then recruits T R-I (ALK5). The incorporation of the type I and II receptors into a close spatial arrangement leads to activation of these receptor complexes resulting from the phosphorylation of the type I receptor by the constitutively active type II receptor. Receptor activation leads to the phosphorylation of a family of cytoplasmic proteins which were initially identified in Drosophila and termed mothers against decapentaplegic (Mad), the vertebrate homologues of which are the so-called Smads.10 Eight Smad members are known in mammals, classified into 3 different groups based on structure and function: receptorregulated Smads (R-Smad), which include Smads 1, 2, 3, 5, and 8; a common-mediator Smad (co-Smad), Smad4; and Inhibitory (I) Smads 6 and 7. The signaling from the T RI-RII complex is mediated by Smads 2 and 3. In endothelial cells, an alternate receptor–ligand complex can be formed with ALK1 as the type I receptor, which employs Smads 1 and 5. A balance between the two signaling pathways, which lead to the activation of different sets of genes, may constitute an on/off switch for the control of angiogenesis.8 In both cases, phosphorylation of the R-Smad results in increased association with Smad4 (Co-Smad) and translocation of the complex to the nucleus. Another level of complexity is introduced by the existence of two functional Smad domains, MH1 and MH2, which interact, often in opposite ways, to regulate gene transcription. Although both domains can interact with a wide variety of nuclear proteins involved in transcriptional regulation, MH1 can also bind to Smad-binding element of the DNA directly. The existence of different transcription factors and cofactors in various cell types has been shown to account for some of the cellspecificity of TGFresponses.10 There are several intricate layers of regulation of TGFsignaling which include inhibition of the extracellular receptor binding of TGF(and other members of this superfamily) by soluble proteins (ie, decorin, 2-macroglobulin, and Noggin), the presence of membrane anchored accessory (ie, betaglycan, endoglin) or decoy receptors (ie, BAMBI), as well as intracellular proteins, such as FKBP12 which binds to the unphosphorylated GS domain of type I receptors thus reducing basal activity. A further level of complexity is provided by the mechanisms of inactivation of Smad signaling, which involve both additional phosphorylation and dephosphorylation by as yet poorly understood phosphatases, as well as ubiquination. A diverse range of cytoplasmic kinases have been shown to phosphorylate the linker regions of R-Smads, inhibiting ligand-induced nuclear translocation.10,11 Ubiquination involves a family of E3 ubiquitin ligases, the Smad ubiquination regulatory factors (Smurfs) which target the activated R-Smads and TGFreceptors to the proteasome for degradation. Again the precise mechanisms vary for the signaling pathways of various members of the TGFsuperfamily: Smurf1 targets Smads 1 and 5 for destruction in the cytoplasm of unstimulated cells, whereas activated Smad2 is ubiquinated in the nucleus by a Smurf2dependent mechanism.12 The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Terrence Donnelly Research Laboratories, Division of Cardiology, St. Michael’s Hospital (P.F.H.L., D.W.C., D.J.S.), the Institute of Medical Science (P.F.H.L., D.J.S.), and the McLaughlin Centre for Molecular Medicine (D.J.S.), University of Toronto, Ontario, Canada. Correspondence to Duncan J. Stewart, MD, FRCPC, FAHA, Professor of Medicine and Dexter H.C. Man Chair of Cardiology, University of Toronto, Room 6-050k, Queen Wing, Terrence Donnelly Heart Centre, St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario, Canada. M5B 1W8. E-mail [email protected] (Circ Res. 2005;97:1087-1089.) © 2005 American Heart Association, Inc.