Arginine methylation of R81 in Smad6 confines BMP-induced Smad1 signaling.
Arginine methylation of R81 in Smad6 confines BMP-induced Smad1 signaling.
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Smad6 中 R81 的精氨酸甲基化限制了 BMP 诱导的 Smad1 信号传导
DOI：
10.1016/j.jbc.2021.100496
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Wu J;Chen X;Sehgal P;Zhang T;Jackson-Weaver O;Gou Y;Bautch V;Frenkel B;Sun H;Xu J
骨形态发生蛋白（BMPs）由多种细胞类型分泌，已知在骨、软骨、肌肉、血管和神经元组织中的细胞分化和基质形成中发挥重要作用。BMP通过Smad 1、Smad 5和Smad 9的C-末端磷酸化激活细胞内效应物，其通过与Smad 4形成复合物并易位到细胞核进行转录激活来传递信号。Smad 6通过在膜、胞质和核水平上的多种机制抑制BMP信号传导。然而，Smad 6功能多样性的机制基础仍不清楚。在这里，使用生物化学方法和细胞分化系统，我们报告了Smad 6的细胞溶质作用机制，需要精氨酸甲基化在精氨酸81（R81）和功能，通过与Smad 1和干扰Smad 1-Smad 4复合物的形成。通过突变甲基化精氨酸残基R81，并通过沉默蛋白质精氨酸甲基转移酶1的表达，我们表明，蛋白质精氨酸甲基转移酶1催化BMP处理后Smad 6的R81甲基化，R81甲基化随后促进Smad 6与磷酸化活性Smad 1的相互作用，R81甲基化促进Smad 6介导的Smad 1-Smad 4复合物形成和核转位的中断。此外，Smad 6 WT，而不是甲基化缺陷的R81 A突变体抑制BMP反应性转录，减弱BMP介导的成骨分化，并拮抗BMP介导的细胞侵袭抑制。综上所述，我们的研究结果表明，R81甲基化在Smad 6介导的BMP反应抑制中起着至关重要的作用。
Bone morphogenetic proteins (BMPs) secreted by a variety of cell types are known to play essential roles in cell differentiation and matrix formation in the bone, cartilage, muscle, blood vessel, and neuronal tissue. BMPs activate intracellular effectors via C-terminal phosphorylation of Smad1, Smad5, and Smad9, which relay the signaling by forming a complex with Smad4 and translocate to the nucleus for transcriptional activation. Smad6 inhibits BMP signaling through diverse mechanisms operative at the membrane, cytosolic, and nuclear levels. However, the mechanistic underpinnings of Smad6 functional diversity remain unclear. Here, using a biochemical approach and cell differentiation systems, we report a cytosolic mechanism of action for Smad6 that requires arginine methylation at arginine 81 (R81) and functions through association with Smad1 and interference with the formation of Smad1–Smad4 complexes. By mutating the methylated arginine residue, R81, and by silencing the expression of protein arginine methyltransferase 1, we show that protein arginine methyltransferase 1 catalyzes R81 methylation of Smad6 upon BMP treatment, R81 methylation subsequently facilitates Smad6 interaction with the phosphorylated active Smad1, and R81 methylation facilitates Smad6-mediated interruption of Smad1–Smad4 complex formation and nuclear translocation. Furthermore, Smad6 WT but not the methylation-deficient R81A mutant inhibited BMP-responsive transcription, attenuated BMP-mediated osteogenic differentiation, and antagonized BMP-mediated inhibition of cell invasion. Taken together, our results suggest that R81 methylation plays an essential role in Smad6-mediated inhibition of BMP responses.
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DOI：
10.1083/jcb.200106023
发表时间：
2001-12-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hanyu A;Ishidou Y;Ebisawa T;Shimanuki T;Imamura T;Miyazono K
通讯作者：
Miyazono K
影响因子：
1.5
作者：
Timberlake AT;Wu R;Nelson-Williams C;Furey CG;Hildebrand KI;Elton SW;Wood JS;Persing JA;Lifton RP
通讯作者：
Lifton RP
影响因子：
7.2
作者：
Katagiri, Takenobu;Watabe, Tetsuro
通讯作者：
Watabe, Tetsuro
影响因子：
16
作者：
Le Romancer, Muriel;Treilleux, Isabelle;Corbo, Laura
通讯作者：
Corbo, Laura
影响因子：
4.8
作者：
Bai, ST;Shi, XM;Cao, X
通讯作者：
Cao, X