R-SMAD

Abstract: Transforming growth factor-beta (TGF-beta) proteins regulate cell function, and have key roles in development and carcinogenesis The intracellular effectors of TGF-beta signalling, the Smad proteins, are activated by receptors and translocate into the nucleus, where they regulate transcription Although this pathway is inherently simple, combinatorial interactions in the heteromeric receptor and Smad complexes, receptor-interacting and Smad-interacting proteins, and cooperation with sequence-specific transcription factors allow substantial versatility and diversification of TGF-beta family responses Other signalling pathways further regulate Smad activation and function In addition, TGF-beta receptors activate Smad-independent pathways that not only regulate Smad signalling, but also allow Smad-independent TGF-beta responses

Abstract: The recent identification of the SMAD family of signal transducer proteins has unravelled the mechanisms by which transforming growth factor-beta (TGF-beta) signals from the cell membrane to the nucleus. Pathway-restricted SMADs are phosphorylated by specific cell-surface receptors that have serine/threonine kinase activity, then they oligomerize with the common mediator Smad4 and translocate to the nucleus where they direct transcription to effect the cell's response to TGF-beta. Inhibitory SMADs have been identified that block the activation of these pathway-restricted SMADs.

Abstract: Transforming growth factor-β (TGF-β) signals by contacting two distantly related transmem-brane serine/threonine kinases called receptors I and II. The role of these molecules in signalling has now been determined. TGF-β binds directly to receptor II, which is a constitutively active kinase. Bound TGF-β is then recognized by receptor I which is recruited into the complex and becomes phosphorylated by receptor II. Phosphorylation allows receptor I to propagate the signal to downstream substrates. This provides a mechanism by which a cytokine can generate the first step of a signalling cascade.

Abstract: The deployment of a cell's genetic program in a multicellular organism must be tightly controlled for the sake of the organism as a whole. Over the past 20 years the transforming growth factor‐β (TGF‐β) family of secretory polypeptides has emerged as a major source of signals exerting this type of control. This family includes various forms of TGF‐β, the bone morphogenetic proteins (BMPs), the Nodals, the Activins, the anti‐Mullerian hormone, and many other structurally related factors in vertebrates, insects and nematodes (Massague, 1998). Produced by diverse cell types, these factors regulate cell migration, adhesion, multiplication, differentiation and death throughout the life span of the organism. Many of these responses result from changes in the expression of key target genes. Hence, transcriptional control by the TGF‐β family has become a subject of intense investigation in recent years. The present knowledge of these mechanisms is reviewed here. One basic concept concerning the role of the TGF‐β family as hormonally active agents warrants mention at the outset. Unlike classical hormones, whose actions are few and concrete, the members of the TGF‐β family have many different effects depending on the type and state of the cell. For example, in the same healing wound TGF‐β may stimulate or inhibit cell proliferation depending on whether the target is a fibroblast or a keratinocyte (Ashcroft et al ., 1999); in mammary epithelial cells TGF‐β will cause growth arrest or metastatic behavior depending on the level of oncogenic Ras activity present in the cell (Oft et al ., 1996); and human BMP4 and its Drosophila ortholog, DPP, can signal dorsalization in the fly (Padgett et al ., 1993) yet bone formation in a vertebrate (Sampath et al ., 1993). TGF‐β family members are multifunctional hormones, the nature of their effects depending on what has been called ‘the cellular context’. It was plausible …