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      Matters of context guide future research in TGFβ superfamily signaling.

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          Abstract

          The highly conserved wiring of the SMAD-dependent transforming growth factor β (TGFβ) superfamily signaling pathway has been mapped over the last 20 years after molecular discovery of its component parts. Numerous alternative TGFβ-activated signaling pathways that elicit SMAD-independent biological responses also exist. However, the molecular mechanisms responsible for the renowned context dependency of TGFβ signaling output remains an active and often confounding area of research, providing a prototype relevant to regulation of other signaling pathways. Highlighting discoveries presented at the 9th FASEB meeting, The TGFβ Superfamily: Signaling in Development and Disease (July 12-17th 2015 in Snowmass, Colorado), this Review outlines research into the rich contextual nature of TGFβ signaling output and offers clues for therapeutic advances.

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          Most cited references88

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          The Amphimedon queenslandica genome and the evolution of animal complexity.

          Sponges are an ancient group of animals that diverged from other metazoans over 600 million years ago. Here we present the draft genome sequence of Amphimedon queenslandica, a demosponge from the Great Barrier Reef, and show that it is remarkably similar to other animal genomes in content, structure and organization. Comparative analysis enabled by the sequencing of the sponge genome reveals genomic events linked to the origin and early evolution of animals, including the appearance, expansion and diversification of pan-metazoan transcription factor, signalling pathway and structural genes. This diverse 'toolkit' of genes correlates with critical aspects of all metazoan body plans, and comprises cell cycle control and growth, development, somatic- and germ-cell specification, cell adhesion, innate immunity and allorecognition. Notably, many of the genes associated with the emergence of animals are also implicated in cancer, which arises from defects in basic processes associated with metazoan multicellularity.
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            Latent TGF-β structure and activation.

            Transforming growth factor (TGF)-β is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-β1 requires the binding of α(v) integrin to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-β binding proteins. Crystals of dimeric porcine proTGF-β1 reveal a ring-shaped complex, a novel fold for the prodomain, and show how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between α(v)β(6) integrin and the prodomain is insufficient for TGF-β1 release. Force-dependent activation requires unfastening of a 'straitjacket' that encircles each growth-factor monomer at a position that can be locked by a disulphide bond. Sequences of all 33 TGF-β family members indicate a similar prodomain fold. The structure provides insights into the regulation of a family of growth and differentiation factors of fundamental importance in morphogenesis and homeostasis.
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              The Trichoplax genome and the nature of placozoans.

              As arguably the simplest free-living animals, placozoans may represent a primitive metazoan form, yet their biology is poorly understood. Here we report the sequencing and analysis of the approximately 98 million base pair nuclear genome of the placozoan Trichoplax adhaerens. Whole-genome phylogenetic analysis suggests that placozoans belong to a 'eumetazoan' clade that includes cnidarians and bilaterians, with sponges as the earliest diverging animals. The compact genome shows conserved gene content, gene structure and synteny in relation to the human and other complex eumetazoan genomes. Despite the apparent cellular and organismal simplicity of Trichoplax, its genome encodes a rich array of transcription factor and signalling pathway genes that are typically associated with diverse cell types and developmental processes in eumetazoans, motivating further searches for cryptic cellular complexity and/or as yet unobserved life history stages.
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                Author and article information

                Journal
                Sci Signal
                Science signaling
                American Association for the Advancement of Science (AAAS)
                1937-9145
                1945-0877
                Oct 20 2015
                : 8
                : 399
                Affiliations
                [1 ] Helen Diller Family Comprehensive Cancer Center and Department of Anatomy, University of California at San Francisco, San Francisco, CA 94158-9001, USA. rosemary.akhurst@ucsf.edu.
                [2 ] Waksman Institute, Department of Molecular Biology and Biochemistry, and Cancer Institute of New Jersey, Rutgers University, Piscataway, NJ 08854-8020, USA.
                Article
                8/399/re10
                10.1126/scisignal.aad0416
                26486175
                b117c32e-f43b-4ea7-b130-a569f88571c6
                History

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