{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T11:18:15Z","timestamp":1791026295827,"version":"4.1.0"},"reference-count":69,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"23","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. STKE"],"published-print":{"date-parts":[[2000,3,14]]},"abstract":"<jats:p>The transforming growth factor\u2013\u03b2 (TGF-\u03b2) superfamily of secreted polypeptide growth factors exerts extensive control over all aspects of development and homeostasis, and components of this pathway are often mutated in cancers and in several hereditary disorders. Apart from TGF-\u03b2, the superfamily also includes the activins and the bone morphogenetic proteins. These factors signal through heteromeric complexes of type II and type I serine-threonine kinase receptors, which activate the downstream Smad signal transduction pathway. Three classes of Smads have been defined: the receptor-regulated Smads (R-Smads), the common-mediator Smads (co-Smads), and the antagonistic or inhibitory Smads (I-Smads). Receptor complexes activate the Smad pathway by interacting and phosphorylating specific R-Smads. Phosphorylation of the R-Smads causes dissociation from the receptor and induces assembly into complexes with Smad4, a co-Smad. This heteromeric complex then translocates into the nucleus, where the Smads function as transcriptional comodulators by recruiting coactivators or corepressors to Smad DNA binding partners. Thus, Smads transmit signals directly from the receptor kinase into the nucleus. Crosstalk between Smads and other signaling pathways occurs both in the cytosol and in the nucleus. In the cytosol, Smad translocation might be inhibited by mitogen-activated protein kinase\u2013dependent phosphorylation, whereas in the nucleus Smads interact with a number of transcription factors that themselves are primary targets of other signaling pathways. Furthermore, Smad-dependent regulation of these targets often requires input from the primary signaling pathway. In these examples, Smad signaling may represent a secondary signal that modifies the output of the primary pathway. Consequently, the transcriptional response to TGF-\u03b2 family ligands may be dependent on what other signals are being received by the cell. Crosstalk may thus provide one explanation for the long-standing observation that the biological response to TGF-\u03b2 is often dependent on the extracellular environment of the cell.<\/jats:p>","DOI":"10.1126\/stke.2000.23.re1","type":"journal-article","created":{"date-parts":[[2003,5,10]],"date-time":"2003-05-10T00:47:47Z","timestamp":1052527667000},"source":"Crossref","is-referenced-by-count":39,"title":["Crossing Smads"],"prefix":"10.1126","volume":"2000","author":[{"given":"Jeffrey L.","family":"Wrana","sequence":"first","affiliation":[{"name":"Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and Department of Medical Genetics and Microbiology, University of Toronto, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/37284"},{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(98)80141-5"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81696-7"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.67.1.753"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.12.16.2445"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/383691a0"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/38008"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80119-7"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.23.3157"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80120-3"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.37.26584"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1998.9170"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/17826"},{"key":"e_1_3_1_14_2","first-page":"257","volume":"6","year":"1998","unstructured":"Hata, A., Shi, Y., and Massagu\u00e9, J. 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