Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520-8023, USA.
Mol Cancer Res. 2010 Oct;8(10):1388-98. doi: 10.1158/1541-7786.MCR-10-0042. Epub 2010 Sep 21.
ErbB4 is unusual among receptor tyrosine kinases because some isoforms can be efficiently cleaved at the plasma membrane to release a soluble intracellular domain. The cleavage product has high kinase activity and homes to the nucleus. A screen for proteins that associate with the ErbB4 intracellular domain identified candidate interactors including ITCH, WWP2, Nucleolin, and Krab-associated protein 1 (Kap1). Kap1 binds to multiple isoforms of ErbB4 but does not require ErbB4 kinase activity for binding, nor is it an ErbB4 substrate. Kap1 reduces ERBB4 transcription and either directly or indirectly modulates the expression of genes that are themselves regulated by ErbB4. Upregulation of ErbB4 and suppression of MDM2 jointly enhance and accelerate the accumulation of p21(CIP1) in response to DNA damage. Overall, these findings further substantiate the role of ErbB4 in conjoint regulation of growth factor signaling and DNA damage responses.
表皮生长因子受体 4（ErbB4）属于受体酪氨酸激酶，它有一个独特之处，即部分异构体可以在质膜上被有效切割，释放出可溶性的细胞内结构域。该切割产物具有较高的激酶活性，并能向核内转移。一项针对与 ErbB4 细胞内结构域相关蛋白的筛选发现了候选相互作用蛋白，包括 E3 泛素连接酶ITCH、WWP2、核仁蛋白和 Krab 相关蛋白 1（Kap1）。Kap1 可以与 ErbB4 的多种异构体结合，但结合并不依赖于 ErbB4 的激酶活性，Kap1 也不是 ErbB4 的底物。Kap1 可以降低 ERBB4 的转录水平，并直接或间接调节由 ErbB4 调控的基因的表达。上调 ErbB4 并抑制 MDM2 可共同增强并加速 p21(CIP1)在 DNA 损伤时的积累。总的来说，这些发现进一步证实了 ErbB4 在共同调节生长因子信号和 DNA 损伤反应中的作用。
