Ciraolo Elisa, Iezzi Manuela, Marone Romina, Marengo Stefano, Curcio Claudia, Costa Carlotta, Azzolino Ornella, Gonella Cristiano, Rubinetto Cristina, Wu Haiyan, Dastrù Walter, Martin Erica L, Silengo Lorenzo, Altruda Fiorella, Turco Emilia, Lanzetti Letizia, Musiani Piero, Rückle Thomas, Rommel Christian, Backer Jonathan M, Forni Guido, Wymann Matthias P, Hirsch Emilio
Department of Genetics, Biology and Biochemistry, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
Sci Signal. 2008 Sep 9;1(36):ra3. doi: 10.1126/scisignal.1161577.
The phosphoinositide 3-kinase (PI3K) pathway crucially controls metabolism and cell growth. Although different PI3K catalytic subunits are known to play distinct roles, the specific in vivo function of p110beta (the product of the PIK3CB gene) is not clear. Here, we show that mouse mutants expressing a catalytically inactive PIK3CB(K805R) mutant survived to adulthood but showed growth retardation and developed mild insulin resistance with age. Pharmacological and genetic analyses of p110beta function revealed that p110beta catalytic activity is required for PI3K signaling downstream of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors as well as to sustain long-term insulin signaling. In addition, PIK3CB(K805R) mice were protected in a model of ERBB2-driven tumor development. These findings indicate an unexpected role for p110beta catalytic activity in diabetes and cancer, opening potential avenues for therapeutic intervention.
磷酸肌醇-3激酶（PI3K）信号通路对新陈代谢和细胞生长起着至关重要的调控作用。尽管已知不同的PI3K催化亚基发挥着不同的作用，但p110β（PIK3CB基因的产物）在体内的具体功能尚不清楚。在此，我们发现表达催化失活型PIK3CB（K805R）突变体的小鼠突变体能够存活至成年，但随着年龄增长出现生长迟缓并发展出轻度胰岛素抵抗。对p110β功能的药理学和遗传学分析表明，p110β催化活性对于异三聚体鸟嘌呤核苷酸结合蛋白（G蛋白）偶联受体下游的PI3K信号传导以及维持长期胰岛素信号传导是必需的。此外，在ERBB2驱动的肿瘤发生模型中，PIK3CB（K805R）小鼠受到了保护。这些发现表明p110β催化活性在糖尿病和癌症中具有意想不到的作用，为治疗干预开辟了潜在途径。
