title: Non-Smad signaling pathways.
abstract: Transforming growth factor-beta (TGFβ) is a key regulator of cell fate during embryogenesis and has also emerged as a potent driver of the epithelial-mesenchymal transition during tumor progression. TGFβ signals are transduced by transmembrane type I and type II serine/threonine kinase receptors (TβRI and TβRII, respectively). The activated TβR complex phosphorylates Smad2 and Smad3, converting them into transcriptional regulators that complex with Smad4. TGFβ also uses non-Smad signaling pathways such as the p38 and Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways to convey its signals. Ubiquitin ligase tumor necrosis factor (TNF)-receptor-associated factor 6 (TRAF6) and TGFβ-associated kinase 1 (TAK1) have recently been shown to be crucial for the activation of the p38 and JNK MAPK pathways. Other TGFβ-induced non-Smad signaling pathways include the phosphoinositide 3-kinase-Akt-mTOR pathway, the small GTPases Rho, Rac, and Cdc42, and the Ras-Erk-MAPK pathway. Signals induced by TGFβ are tightly regulated and specified by post-translational modifications of the signaling components, since they dictate the subcellular localization, activity, and duration of the signal. In this review, we discuss recent findings in the field of TGFβ-induced responses by non-Smad signaling pathways.
authors.affiliation: Medical Biosciences, Umeå University, SE-901 85 Umeå, Sweden.
authors.forename: Yabing
authors.initials: Y
authors.lastname: Mu
authors.forename: Shyam Kumar
authors.initials: SK
authors.lastname: Gudey
authors.forename: Maréne
authors.initials: M
authors.lastname: Landström
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D048049:Extracellular Signal-Regulated MAP Kinases; D020558:GTP Phosphohydrolases; D016023:Integrins; D020930:MAP Kinase Kinase Kinases; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D048029:TNF Receptor-Associated Factor 6; D016212:Transforming Growth Factor beta; D000099151:MAP Kinase Kinase Kinase 7; C499657:PARD6A protein, human