Phosphorylation-dependent interaction between tumor suppressors Dig and Lgl

• Published in: 细胞研究：英文版 2014 (4), p.451-463
• Main Author: Jinwei Zhu Yuan Shang Qingwen Wan Yitian Xia Jia Chen Quansheng Du Mingjie Zhang
• Format: Article
• Language: English
• Subjects: 分子机制; 后生动物; 挖掘; 相互作用; 磷酸化; 细胞极性; 肿瘤抑制基因; 自由曲线
• ISSN: 1001-0602; 1748-7838

The tumor suppressors Discs Large （Dig）, Lethal giant larvae （Lgl） and Scribble are essential for the establishment and maintenance of epithelial cell polarity in metazoan. Dig, Lgl and Scribble are known to interact strongly with each other genetically and form the evolutionarily conserved Scribble complex. Despite more than a decade of extensive research, it has not been demonstrated whether Dig, Lgl and Scribble physically interact with each other. Here, we show that Dig directly interacts with Lgl in a phosphorylation-dependent manner. Phosphorylation of any one of the three conserved Ser residues situated in the central linker region of Lgl is sufficient for its binding to the Dig guanylate kinase （GK） domain. The crystal structures of the Dig4 GK domain in complex with two phosphor- Lgl2 peptides reveal the molecular mechanism underlying the specific and phosphorylation-dependent Dlg/Lgl complex formation. In addition to providing a mechanistic basis underlying the regulated formation of the Scribble complex, the structure of the Dlg/Lgl complex may also serve as a starting point for designing specific Dig inhibitors for targeting the Scribble complex formation.