Fine Tuning and Cross-talking of TGF-β Signal by Inhibitory Smads
نویسنده
چکیده
Transforming Growth Factor (TGF)-β family, including TGF-β, bone morphorgenic protein (BMP), and activn, plays an important role in essential cellular functions such as proliferation, differentiation, apoptosis, tissue remodeling, angiognesis, immune responses, and cell adhesions. TGF-β predominantly transmits the signals through serine/ threonine receptor kinases and cytoplasmic proteins called Smads. Since the discovery of TGF-β in the early 1980s, the dysregulation of TGF-β/Smad signaling has been implicated in the pathogenesis of human diseases. Among signal transducers in TGF-β/Smad signaling, inhibitory Smads (I-Smads), Smad6 and Smad7, act as major negative regulators forming autoinhibitory feedback loops and mediate the cross-talking with other signaling pathways. Expressions of I-Smads are mainly regulated on the transcriptional levels and post-translational protein degradations and their intracellular levels are tightly controlled to maintain the homeostatic balances. However, abnormal levels of I-Smads in the pathological conditions elicit the altered TGF-β signaling in cells, eventually causing TGF-β-related human diseases. Thus, exploring the molecular mechanisms about the regulations of ISmads may provide the therapeutic clues for human diseases induced by the abnormal TGF-β signaling.
منابع مشابه
Posttranslational Regulation of Smads.
Transforming growth factor β (TGF-β) family signaling dictates highly complex programs of gene expression responses, which are extensively regulated at multiple levels and vary depending on the physiological context. The formation, activation, and destruction of two major functional complexes in the TGF-β signaling pathway (i.e., the TGF-β receptor complexes and the Smad complexes that act as c...
متن کاملReversible ubiquitination regulates the Smad/TGF-β signalling pathway
TGF-β (transforming growth factor-β) signals through serine/threonine kinase receptors and intracellular Smad transcription factors. An important regulatory step involves specific ubiquitination by Smurfs (Smad– ubiquitin regulatory factors), members of the HECT (homologous to E6-associated protein C-terminus) ubiquitin ligase family, which mediate the proteasomal degradation of Smads and/or re...
متن کاملRegulation of TGF-β signal transduction by mono- and deubiquitylation of Smads.
Polyubiquitylation leading to proteasomal degradation is a well-established mechanism for regulating TGF-β signal transduction components such as receptors and Smads. Recently, an equally important role was suggested for monoubiquitylation of both Smad4 and receptor-associated Smads that regulates their function without protein degradation. Monoubiquitylation of Smads was discovered following t...
متن کاملMembrane targeting of inhibitory Smads through palmitoylation controls TGF-β/BMP signaling
TGF-β/BMP (bone morphogenetic protein) signaling pathways play conserved roles in controlling embryonic development, tissue homeostasis, and stem cell regulation. Inhibitory Smads (I-Smads) have been shown to negatively regulate TGF-β/BMP signaling by primarily targeting the type I receptors for ubiquitination and turnover. However, little is known about how I-Smads access the membrane to execu...
متن کاملThe N domain of Smad7 is essential for specific inhibition of transforming growth factor-β signaling
Inhibitory Smads (I-Smads) repress signaling by cytokines of the transforming growth factor-beta (TGF-beta) superfamily. I-Smads have conserved carboxy-terminal Mad homology 2 (MH2) domains, whereas the amino acid sequences of their amino-terminal regions (N domains) are highly divergent from those of other Smads. Of the two different I-Smads in mammals, Smad7 inhibited signaling by both TGF-be...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره شماره
صفحات -
تاریخ انتشار 2005