Antagonistic effects of protein kinase C alpha and delta on both transformation and phospholipase D activity mediated by the epidermal growth factor receptor.
Antagonistic effects of protein kinase C alpha and delta on both transformation and phospholipase D activity mediated by the epidermal growth factor receptor.
复制标题
蛋白激酶 C α 和 δ 对表皮生长因子受体介导的转化和磷脂酶 D 活性的拮抗作用。
DOI：
10.1128/mcb.19.11.7672
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发表时间：
1999
影响因子：
5.3
通讯作者：
Foster,DA
中科院分区：
文献类型：
--
作者：
Hornia,A;Lu,Z;Sukezane,T;Zhong,M;Joseph,T;Frankel,P;Foster,DA
通过促进肿瘤的佛波酯12-O-十四酰佛波醇-13-乙酸酯(TPA)下调蛋白激酶Cδ(PKCδ)，可以转化过度表达非受体类酪氨酸激酶C-Src的细胞(Z.Lu等，Mol.牢房。比奥尔。17：3418-3428,1997)。我们将这些研究扩展到高表达受体类酪氨酸激酶的细胞，即表皮生长因子(EGF)受体(EGFR细胞)；像c-Src一样，EGF受体在几个人类肿瘤中过表达。与预期相反，TPA下调PKC亚型并没有改变EGFR细胞；然而，EGF治疗确实改变了这些细胞。由于TPA下调所有佛波酯反应的蛋白激酶C亚型，我们研究了蛋白激酶Cδ和蛋白激酶Cα特异性抑制剂的作用以及蛋白激酶Cδ和α的显性负突变的表达。与PKCδ的肿瘤抑制功能一致的是，PKCδ的特异性抑制剂rotlerin和一个显性的负PKCδ突变体在没有表皮生长因子的情况下转化了EGFR细胞。相反，PKCα特异性抑制剂Go6976和显性负性PKCα突变体的表达阻断了由表皮生长因子和PKCδ抑制所诱导的转化表型。有趣的是，rotlerin和EGF都诱导磷脂酶D(PLD)活性显著增加，这种活性通常在有丝分裂刺激下升高。抑制PKCδ的转化后，PLD活性的升高依赖于PKCα，且仅限于EGFR细胞。这些数据表明，PKC亚型α和δ对转化和PLD活性都有拮抗作用，并进一步支持了PKCδ的肿瘤抑制作用，这种作用可能是通过抑制依赖酪氨酸激酶的PLD活性的增加而实现的。
Downregulation of protein kinase C δ (PKC δ) by treatment with the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) transforms cells that overexpress the non-receptor class tyrosine kinase c-Src (Z. Lu et al., Mol. Cell. Biol. 17:3418–3428, 1997). We extended these studies to cells overexpressing a receptor class tyrosine kinase, the epidermal growth factor (EGF) receptor (EGFR cells); like c-Src, the EGF receptor is overexpressed in several human tumors. In contrast with expectations, downregulation of PKC isoforms with TPA did not transform the EGFR cells; however, treatment with EGF did transform these cells. Since TPA downregulates all phorbol ester-responsive PKC isoforms, we examined the effects of PKC δ- and PKC α-specific inhibitors and the expression of dominant negative mutants for both PKC δ and α. Consistent with a tumor-suppressing function for PKC δ, the PKC δ-specific inhibitor rottlerin and a dominant negative PKC δ mutant transformed the EGFR cells in the absence of EGF. In contrast, the PKC α-specific inhibitor Go6976 and expression of a dominant negative PKC α mutant blocked the transformed phenotype induced by both EGF and PKC δ inhibition. Interestingly, both rottlerin and EGF induced substantial increases in phospholipase D (PLD) activity, which is commonly elevated in response to mitogenic stimuli. The elevation of PLD activity in response to inhibiting PKC δ, like transformation, was dependent upon PKC α and restricted to the EGFR cells. These data demonstrate that PKC isoforms α and δ have antagonistic effects on both transformation and PLD activity and further support a tumor suppressor role for PKC δ that may be mediated by suppression of tyrosine kinase-dependent increases in PLD activity.