Cui X, De Vivo I, Slany R, Miyamoto A, Firestein R, Cleary M L
Department of Pathology, Stanford University Medical Center, California 94305, USA.
Nat Genet. 1998 Apr;18(4):331-7. doi: 10.1038/ng0498-331.
Several proteins that contribute to epigenetic mechanisms of gene regulation contain a characteristic motif of unknown function called the SET (Suvar3-9, Enhancer-of-zeste, Trithorax) domain. We have demonstrated that SET domains mediate highly conserved interactions with a specific family of proteins that display similarity with dual-specificity phosphatases (dsPTPases). These include myotubularin, the gene of which is mutated in a subset of patients with X-linked myotubular myopathy, and Sbf1, a newly isolated homologue of myotubularin. In contrast with myotubularin, Sbf1 lacks a functional catalytic domain which dephosphorylates phospho-tyrosine and serine-containing peptides in vitro. Competitive interference of endogenous SET domain-dsPTPase interactions by forced expression of Sbf1 induced oncogenic transformation of NIH 3T3 fibroblasts and impaired the in vitro differentiation of C2 myoblast cells. We conclude that myotubularin-type phosphatases link SET-domain containing components of the epigenetic regulatory machinery with signalling pathways involved in growth and differentiation.
几种参与基因调控表观遗传机制的蛋白质含有一个功能未知的特征基序，称为SET（Suvar3-9、zeste增强子、三体胸苷）结构域。我们已经证明，SET结构域介导与一类特定蛋白质的高度保守相互作用，这类蛋白质与双特异性磷酸酶（dsPTPases）具有相似性。其中包括肌管素，其基因在一部分X连锁肌管性肌病患者中发生突变，以及Sbf1，一种新分离的肌管素同源物。与肌管素不同，Sbf1缺乏一个在体外使含磷酸酪氨酸和丝氨酸的肽去磷酸化的功能性催化结构域。通过强制表达Sbf1对内源性SET结构域-dsPTPase相互作用的竞争性干扰诱导了NIH 3T3成纤维细胞的致癌转化，并损害了C2成肌细胞的体外分化。我们得出结论，肌管素型磷酸酶将表观遗传调控机制中含SET结构域的成分与参与生长和分化的信号通路联系起来。
