SMAD3

Case study 1: Chen Yang, 2021

Macroautophagy/autophagy dysregulation has been noted in diabetic nephropathy; however, the regulatory mechanisms controlling this process remain unclear. In this study, the researchers showed that SMAD3 (SMAD family member 3), the key effector of TGFB (transforming growth factor beta)-SMAD signaling, induces lysosome depletion via the inhibition of TFEB-dependent lysosome biogenesis. The pharmacological inhibition or genetic deletion of SMAD3 restored lysosome biogenesis activity by alleviating the suppression of TFEB, thereby protecting lysosomes from depletion and improving autophagic flux in renal tubular epithelial cells in diabetic nephropathy. Mechanistically, they found that SMAD3 directly binds to the 3'-UTR of TFEB and inhibits its transcription. Silencing TFEB suppressed lysosome biogenesis and resulted in a loss of the protective effects of SMAD3 inactivation on lysosome depletion under diabetic conditions. In conclusion, SMAD3 promotes lysosome depletion via the inhibition of TFEB-dependent lysosome biogenesis; this may be an important mechanism underlying autophagy dysregulation in the progression of diabetic nephropathy.

Fig1. Western blot analysis of phospho-SMAD3, LC3, and SQSTM1 expression in AGE-BSA or Co-BSA-treated HK-2 cells.

Fig2. Western blot analysis of phospho-SMAD3 expression in HK-2 cells.

Case study 2: Heeseog Kang, 2020

Melorheostosis is a rare sclerosing dysostosis characterized by asymmetric exuberant bone formation. Recently, the researchers reported that somatic mosaicism for MAP2K1-activating mutations causes radiographical "dripping candle wax" melorheostosis. They now report somatic SMAD3 mutations in bone lesions of four unrelated patients with endosteal pattern melorheostosis. In vitro, the SMAD3 mutations stimulated the TGF-β pathway in osteoblasts, enhanced nuclear translocation and target gene expression, and inhibited proliferation. Osteoblast differentiation and mineralization were stimulated by the SMAD3 mutation, consistent with higher mineralization in affected than in unaffected bone, but differing from MAP2K1 mutation-positive melorheostosis. Conversely, osteoblast differentiation and mineralization were inhibited when osteogenesis of affected osteoblasts was driven in the presence of BMP2. Transcriptome profiling displayed that TGF-β pathway activation and ossification-related processes were significantly influenced by the SMAD3 mutation. Co-expression clustering illuminated melorheostosis pathophysiology, including alterations in ECM organization, cell growth, and interferon signaling. These data reveal antagonism of TGF-β/SMAD3 activation by BMP signaling in SMAD3 mutation-positive endosteal melorheostosis, which may guide future therapies.

Fig3. SMAD3 phosphorylation upon TGF-β stimulation with or without TGFβRI inhibitor (SB431542) pretreatment was assessed by Western blotting (Melo-11, SMAD3 p.S264Y).

Fig4. Effect of the mutant SMAD3 with low VAF on TGF-β signaling activation. SMAD3 phosphorylation in affected cells of melorheostotic bone in response to TGF-β stimulation was comparable to that in unaffected cells.

Fig1. Smad3 signaling and crosstalk pathways in renal fibrosis. (Wenjing Wu, 2022)

Fig2. Smad3 signaling and crosstalk pathways in renal inflammation. (Wenjing Wu, 2022)

SMAD3 involved in several pathways and played different roles in them. We selected most pathways SMAD3 participated on our site, such as FoxO signaling pathway, Cell cycle, Endocytosis, which may be useful for your reference. Also, other proteins which involved in the same pathway with SMAD3 were listed below. Creative BioMart supplied nearly all the proteins listed, you can search them on our site.

SMAD3 has several biochemical functions, for example, R-SMAD binding, RNA polymerase II activating transcription factor binding, RNA polymerase II core promoter proximal region sequence-specific DNA binding. Some of the functions are cooperated with other proteins, some of the functions could acted by SMAD3 itself. We selected most functions SMAD3 had, and list some proteins which have the same functions with SMAD3. You can find most of the proteins on our site.

SMAD3 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with SMAD3 here. Most of them are supplied by our site. Hope this information will be useful for your research of SMAD3.

SMAD4; SKI