Zhan Xuanzhi, Stoy Henriette, Kaoud Tamer S, Perry Nicole A, Chen Qiuyan, Perez Alejandro, Els-Heindl Sylvia, Slagis Jack V, Iverson Tina M, Beck-Sickinger Annette G, Gurevich Eugenia V, Dalby Kevin N, Gurevich Vsevolod V
Departments of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
University of Tübingen, Tübingen 72074, Germany.
Sci Rep. 2016 Feb 12;6:21025. doi: 10.1038/srep21025.
Three-kinase mitogen-activated protein kinase (MAPK) signaling cascades are present in virtually all eukaryotic cells. MAPK cascades are organized by scaffold proteins, which assemble cognate kinases into productive signaling complexes. Arrestin-3 facilitates JNK activation in cells, and a short 25-residue arrestin-3 peptide was identified as the critical JNK3-binding element. Here we demonstrate that this peptide also binds MKK4, MKK7, and ASK1, which are upstream JNK3-activating kinases. This peptide is sufficient to enhance JNK3 activity in cells. A homologous arrestin-2 peptide, which differs only in four positions, binds MKK4, but not MKK7 or JNK3, and is ineffective in cells at enhancing activation of JNK3. The arrestin-3 peptide is the smallest MAPK scaffold known. This peptide or its mimics can regulate MAPKs, affecting cellular decisions to live or die.
三激酶丝裂原活化蛋白激酶（MAPK）信号级联几乎存在于所有真核细胞中。MAPK级联由支架蛋白组织，支架蛋白将同源激酶组装成有活性的信号复合物。抑制蛋白3促进细胞中的JNK激活，并且一个25个残基的短抑制蛋白3肽被鉴定为关键的JNK3结合元件。在这里，我们证明该肽还结合MKK4、MKK7和ASK1，它们是JNK3上游的激活激酶。该肽足以增强细胞中的JNK3活性。一种仅在四个位置不同的同源抑制蛋白2肽结合MKK4，但不结合MKK7或JNK3，并且在细胞中增强JNK3激活方面无效。抑制蛋白3肽是已知最小的MAPK支架。该肽或其模拟物可调节MAPK，影响细胞的生死抉择。
