title: The interaction of the ErbB4 intracellular domain p80 with α-enolase in the nuclei is associated with the inhibition of the neuregulin1-dependent cell proliferation.
abstract: We have shown that the receptor tyrosine kinase ErbB4 signals neuregulin1-stimulated proliferation of human cells. Some isoforms of ErbB4 are cleaved to release the soluble intracellular domain p80; however, the function of p80 in cell proliferation remained unclear. Here we propose the possibility for p80 as a negative feedback modulator of ErbB4-mediated cell proliferation. Cells exposed to lower doses of neuregulin1 displayed a stimulated proliferation and contained ErbB4 but barely p80. By contrast, cells exposed to its higher doses displayed a suppressed proliferation and contained p80 but barely ErbB4. Analyses with cells overexpressing the p80 wild type and mutants indicated that nuclear p80 inhibits cell proliferation independently of the tyrosine kinase activity. A screen for a novel protein that interacts with p80 identified α-enolase, which is reported as a transcriptional inhibitor for the proliferation-associated c-myc gene. The c-myc mRNA expression was induced by lower doses of neuregulin1 but was suppressed by its higher doses. Subcellular fractionation demonstrated the localization of not only p80 and α-enolase but also the decrease of the functional c-myc amount in the nuclei of cells exposed to higher doses of neuregulin1. These results suggested that p80, which is generated from ErbB4 and translocates to the nuclei, interacts with α-enolase and inhibits neuregulin1-dependent ErbB4-mediated cell proliferation by impairing the c-myc gene transcription.
authors: Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan.
authors: Satomi
authors: S
authors: Yamada
authors: Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan.
authors: Masaki
authors: M
authors: Marutsuka
authors: Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan.
authors: Miyabi
authors: M
authors: Inoue
authors: Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan.
authors: Jidong
authors: J
authors: Zhang
authors: Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan.
authors: Shin-Ichi
authors: S
authors: Abe
authors: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors: Ken-Ichi
authors: K
authors: Ishibashi
authors: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors: Naoto
authors: N
authors: Yamaguchi
authors: Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan.
authors: Ko
authors: K
authors: Eto
keywords: Growth factor; cell proliferation; intracellular domain signaling; receptor tyrosine kinase; transcriptional regulator