Department of Biochemistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
J Membr Biol. 2012 Aug;245(8):495-506. doi: 10.1007/s00232-012-9500-0. Epub 2012 Sep 11.
Attenuation in gap junctional coupling has consistently been associated with induction of rapid or synchronous cell division in normal and pathological conditions. In the case of the v-src oncogene, gating of Cx43 gap junction channels has been linked to both direct phosphorylation of tyrosines (Y247 and 265) and phosphorylation of the serine targets of Erk1/2 (S255, 279 and 282) on the cytoplasmic C-terminal domain of Cx43. However, only the latter has been associated with acute, rather than chronic, gating of the channels immediately after v-src expression, a process that is mediated through a "ball-and-chain" mechanism. In this study we show that, while ERK1/2 is necessary for acute closure of gap junction channels, it is not sufficient. Rather, multiple pathways converge to regulate Cx43 coupling in response to expression of v-src, including parallel signaling through PKC and MEK1/2, with additional positive and negative regulatory effects mediated by PI3 kinase, distinguished by the involvement of Akt.
缝隙连接偶联的衰减与正常和病理条件下快速或同步细胞分裂的诱导一直密切相关。在 v-src 癌基因的情况下，Cx43 缝隙连接通道的门控与 Cx43 细胞质 C 末端结构域上的酪氨酸（Y247 和 265）的直接磷酸化以及 Erk1/2 的丝氨酸靶标（S255、279 和 282）的磷酸化有关。然而，只有后者与 v-src 表达后立即发生的通道的急性而非慢性门控有关，这一过程通过“球链”机制介导。在这项研究中，我们表明，虽然 ERK1/2 对于缝隙连接通道的急性关闭是必需的，但它是不够的。相反，多种途径汇聚在一起，通过表达 v-src 来调节 Cx43 偶联，包括通过 PKC 和 MEK1/2 的平行信号转导，通过 PI3 激酶介导的额外的正调节和负调节作用，其特征在于 Akt 的参与。
