SMAD6

SMAD6

A gene on chromosome 15q21-q22 that encodes a SMAD family protein, named for their similarity to the Drosophila gene Mothers Against Decapentaplegic (MAD), which are signal transducers and transcription modulators of multiple signalling pathways. SMAD6 downregulates BMP and TGF-beta/activin-signalling by binding to regulatory elements in target promoter regions.
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In a recent study, targeted reseguencing of 22 candidate genes using HaloPlex target enrichment in a strictly defined bicuspid aortic valve/thoracic aortic aneurysm cohort was performed, and it was found that the strongest candidate susceptibility gene was SMAD6. According to the study, SMAD6 gene mutations significantly contribute to the etiologies of thoracic aortic aneurysm and bicuspid aortic valve (12).
In contrast, Smad6 and bone morphogenetic protein receptor type-I (BMPR-1) prevent posphorilation-Smad2 and cause disintegration of Smad2 complex [24].
More recently, Western blot analysis also revealed markedly decreased inhibitory SMAD6 (mothers against decapentaplegic homolog 6) levels in patients with LP [3].
In order to abate excessive TGF-[beta] signaling, the activation of SMAD2/3 is inhibited by SMAD6 and SMAD7 [47, 48].
Moreover, A20, which is recruited by Smad6 to TRAF6, plays an important role in inhibition of noncanonical TGF-[beta] signaling [124], indicating its possible regulation of osteoblastogenesis via this main pathway.
To date, eight mammalian Smad proteins have been characterized and are grouped into three functional classes: receptor-activated Smads (R-Smads) including Smad1, Smad2, Smad3, Smad5, and Smad8, common mediator Smad (Smad4), and inhibitory Smads (I-Smads) including Smad6 and Smad7.
(81) showed lower expression of TGF[beta]RI and SMAD2, SMAD4, and SMAD6 mRNA in lesions and non-lesional skin in psoriasis.
On the other hand, genes like ZHX2, ADNP, or SMAD6 present a very high in-degree, while their out-degree is relatively low.
However, inhibitory Smads (Smad6 and Smad7) and receptor regulated Smads could interact through competitive binding to prevent phosphorylation of receptor regulated Smads thereby, blocking the action of TGF-[beta] [13-15].
miR-567 SPTBN1; DUSP1; BCHE; LPHN2 miR-141-3p H3F3B; TCEAL2; MYH10; LHFP; LPHN2; CCL2; KLF9 miR-454-3p DPYSL2; HOXA5; FKBP11; SRPX; EDN1; LDLR; CAV2; BMPR2; SLC2A1 SERPINE2; PLEKHC1; SPTBN1; H3F3B; miR-590-3p TMEM47; TIMP3; COL3A1; CXCL13; ETS2; CELSR3; LPL; SMAD6; BMPR2; LPHN2; SASH1.
Interestingly, activation of the TGF-[sz] pathway also upregulates Smad6 and Smad7 expression, which can deactivate the pathway.[sup][7] Evidence has also shown that Smad2 and Smad7 alleviate fibrosis whereas Smad3 promotes fibrosis.[sup][8] Many miRNAs and their substrates are involved in regulating the TGF-[sz] signal transduction pathway [Table 1].{Table 1}
While Smad2 overexpression showed the similar beneficial effects of GDF15, overexpression of Smad6 or Smad7 reversed its antihypertrophic effects [78].