Li Yong, Inoki Ken, Vacratsis Panayiotis, Guan Kun-Liang
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor 48109, USA.
J Biol Chem. 2003 Apr 18;278(16):13663-71. doi: 10.1074/jbc.M300862200. Epub 2003 Feb 11.
Tuberous sclerosis complex (TSC) is a genetic disease caused by mutations in either TSC1 or TSC2 tumor suppressor genes. TSC1 and TSC2 (also known as hamartin and tuberin, respectively) form a functional complex and negatively regulate cell growth by inhibiting protein synthesis. 14-3-3 binds to TSC2 and may inhibit TSC2 function. We have reported previously that phosphorylation of serine 1210 (Ser(1210)) in TSC2 is essential for 14-3-3 binding. Here we show that serum and anisomycin enhance the interaction between TSC2 and 14-3-3 by stimulating phosphorylation of Ser(1210). Activation of p38 MAP kinase (p38) is essential for the stimulating effect of serum and anisomycin although p38 is not directly responsible for the phosphorylation of Ser(1210) in TSC2. Both in vitro and in vivo experiments demonstrate that the p38-activated kinase MK2 (also known as MAPKAPK2) is directly responsible for the phosphorylation of Ser(1210). Our data show that anisomycin stimulates phosphorylation of Ser(1210) of TSC2 via the p38-MK2 kinase cascade. Phosphorylation of TSC2 by MK2 creates a 14-3-3 binding site and thus regulates the cellular function of the TSC2 tumor suppressor protein.
结节性硬化症（TSC）是一种由TSC1或TSC2肿瘤抑制基因发生突变引起的遗传性疾病。TSC1和TSC2（分别也称为错构瘤蛋白和结节蛋白）形成一个功能复合物，并通过抑制蛋白质合成来负向调节细胞生长。14-3-3与TSC2结合并可能抑制TSC2的功能。我们之前报道过，TSC2中丝氨酸1210（Ser(1210)）的磷酸化对于14-3-3的结合至关重要。在此我们表明，血清和茴香霉素通过刺激Ser(1210)的磷酸化来增强TSC2与14-3-3之间的相互作用。p38丝裂原活化蛋白激酶（p38）的激活对于血清和茴香霉素的刺激作用至关重要，尽管p38并不直接负责TSC2中Ser(1210)的磷酸化。体外和体内实验均表明，p38激活的激酶MK2（也称为丝裂原活化蛋白激酶激活的蛋白激酶2）直接负责Ser(1210)的磷酸化。我们的数据表明，茴香霉素通过p38-MK2激酶级联反应刺激TSC2的Ser(1210)磷酸化。MK2对TSC2的磷酸化产生一个14-3-3结合位点，从而调节TSC2肿瘤抑制蛋白的细胞功能。
