Beckwith M, Fenton R G, Katona I M, Longo D L
Biological Carcinogenesis and Development Program, Science Applications International Corporation/Frederick, MD, USA.
Blood. 1996 Jan 1;87(1):202-10.
Stimulation of B lymphocytes through the Ig receptor initiates a cascade of biochemical changes, which can ultimately lead to either activation and growth, or cell-cycle arrest and cell death. One of the critical events that occurs in both cases is the activation of tyrosine kinases, and the resulting phosphorylation of a variety of proteins on tyrosine residues. In this report we identify one of the substrates of phosphorylation as the 85-kD subunit of the enzyme phosphatidylinositol-3 kinase (PI3K), and show that both anti-IgM and anti-IgD stimulation results in an increase in the anti-phosphotyrosine-precipitable PI3K activity. Furthermore, we show that the potent and specific inhibitor of PI3K, Wortmannin, can completely abrogate anti-Ig-mediated growth inhibition without affecting tyrosine kinase induction or protein kinase C (PKC) activation. Treatment of intact cells with Wortmannin results in an irreversible decrease in anti-Ig-induced PI3K activity, suggesting that the effect of Wortmannin on anti-Ig-mediated growth inhibition is caused by its inactivation of PI3K activity. Taken together, these data show that activation of PI3K is a critical component of the anti-Ig-initiated signaling cascade that leads to growth inhibition of human B lymphoma cells.
通过Ig受体刺激B淋巴细胞会引发一系列生化变化，最终可能导致激活与生长，或者细胞周期停滞和细胞死亡。在这两种情况下发生的关键事件之一是酪氨酸激酶的激活，以及多种蛋白质酪氨酸残基的磷酸化。在本报告中，我们确定磷酸化的底物之一为磷脂酰肌醇-3激酶（PI3K）的85-kD亚基，并表明抗IgM和抗IgD刺激均会导致抗磷酸酪氨酸沉淀的PI3K活性增加。此外，我们表明PI3K的强效特异性抑制剂渥曼青霉素可以完全消除抗Ig介导的生长抑制，而不影响酪氨酸激酶的诱导或蛋白激酶C（PKC）的激活。用渥曼青霉素处理完整细胞会导致抗Ig诱导的PI3K活性不可逆地降低，这表明渥曼青霉素对抗Ig介导的生长抑制的作用是由其使PI3K活性失活引起的。综上所述，这些数据表明PI3K的激活是抗Ig引发的信号级联反应的关键组成部分，该信号级联反应会导致人B淋巴瘤细胞的生长抑制。
