Shumway Stuart D, Li Yong, Xiong Yue
Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, 27599-7295, USA.
J Biol Chem. 2003 Jan 24;278(4):2089-92. doi: 10.1074/jbc.C200499200. Epub 2002 Dec 4.
TSC2, or tuberin, is the product of the tuberous sclerosis tumor suppressor gene TSC2 and acts downstream of the phosphatidylinositol 3-kinase-Akt signaling pathway to negatively regulate cellular growth. One mechanism underlying its function is to assemble into a heterodimer with the TSC1 gene product TSC1, or hamartin, resulting in a reduction in phosphorylation, and hence activation, of the ribosomal subunit S6 kinase (S6K). We identified a novel interaction between TSC2 and 14-3-3beta. We found that 14-3-3beta does not interfere with TSC1-TSC2 binding and can form a ternary complex with these two proteins. Association between 14-3-3beta and TSC2 requires phosphorylation of TSC2 at a unique residue that is not a known Akt phosphorylation site. The overexpression of 14-3-3beta compromises the ability of the TSC1-TSC2 complex to reduce S6K phosphorylation. The antagonistic activity of 14-3-3beta toward TSC is dependent on the 14-3-3beta-TSC2 interaction, since a mutant of TSC2 that is not recognized by 14-3-3beta is refractory to 14-3-3beta. We suggest that 14-3-3 proteins interact with the TSC1-TSC2 complex and negatively regulate the function of the TSC proteins.
结节性硬化症2（TSC2），即结节蛋白，是结节性硬化症肿瘤抑制基因TSC2的产物，在磷脂酰肌醇3激酶 - 蛋白激酶B（Akt）信号通路的下游发挥作用，对细胞生长进行负调控。其功能的一种潜在机制是与TSC1基因产物TSC1（即错构瘤蛋白）组装成异二聚体，从而导致核糖体亚基S6激酶（S6K）的磷酸化减少，进而激活。我们鉴定出TSC2与14-3-3β之间存在一种新的相互作用。我们发现14-3-3β并不干扰TSC1-TSC2的结合，并且能与这两种蛋白形成三元复合物。14-3-3β与TSC2之间的结合需要TSC2在一个独特的残基处发生磷酸化，该残基并非已知的Akt磷酸化位点。14-3-3β的过表达会损害TSC1-TSC2复合物降低S6K磷酸化的能力。14-3-3β对TSC的拮抗活性依赖于14-3-3β-TSC2的相互作用，因为一个不被14-3-3β识别的TSC2突变体对14-3-3β不敏感。我们认为14-3-3蛋白与TSC1-TSC2复合物相互作用，并对TSC蛋白的功能进行负调控。
