Smeal T, Binetruy B, Mercola D, Grover-Bardwick A, Heidecker G, Rapp U R, Karin M
Department of Pharmacology, University of California, San Diego, School of Medicine, La Jolla 92093-0636.
Mol Cell Biol. 1992 Aug;12(8):3507-13. doi: 10.1128/mcb.12.8.3507-3513.1992.
In resting cells, c-Jun is phosphorylated on five sites. Three of these sites reside next to its DNA binding domain and negatively regulate DNA binding. In response to expression of oncogenic Ha-Ras, phosphorylation of these sites decreases, while phosphorylation of two other sites within c-Jun's activation domain is greatly enhanced. Phosphorylation of these residues, serines 63 and 73, stimulates the transactivation function of c-Jun and is required for oncogenic cooperation with Ha-Ras. We now show that the same changes in c-Jun phosphorylation are elicited by a variety of transforming oncoproteins with distinct biochemical activities. These oncoproteins, v-Sis, v-Src, Ha-Ras, and Raf-1, participate in a signal transduction pathway that leads to increased phosphorylation of serines 63 and 73 on c-Jun. While oncogenic Ha-Ras is a constitutive stimulator of c-Jun activity and phosphorylation, the normal c-Ha-Ras protein is a serum-dependent modulator of c-Jun's activity. c-Jun is therefore a downstream target for a phosphorylation cascade involved in cell proliferation and transformation.
在静息细胞中，c-Jun在五个位点发生磷酸化。其中三个位点位于其DNA结合结构域附近，对DNA结合起负调控作用。响应致癌性Ha-Ras的表达，这些位点的磷酸化减少，而c-Jun激活结构域内另外两个位点的磷酸化则大大增强。这些残基（丝氨酸63和73）的磷酸化刺激c-Jun的反式激活功能，并且是与Ha-Ras发生致癌协同作用所必需的。我们现在表明，多种具有不同生化活性的转化癌蛋白可引发c-Jun磷酸化的相同变化。这些癌蛋白，即v-Sis、v-Src、Ha-Ras和Raf-1，参与一条信号转导途径，该途径导致c-Jun上丝氨酸63和73的磷酸化增加。虽然致癌性Ha-Ras是c-Jun活性和磷酸化的组成型刺激因子，但正常的c-Ha-Ras蛋白是c-Jun活性的血清依赖性调节因子。因此，c-Jun是参与细胞增殖和转化的磷酸化级联反应的下游靶点。
