Department of Molecular Biosciences, University of Texas at Austin, 100 E. 24th St. Stop A5000, Austin, TX 78712, U.S.A.
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, U.S.A.
Biochem J. 2020 Nov 13;477(21):4207-4220. doi: 10.1042/BCJ20200702.
Receptor Tyrosine Kinases (RTKs) comprise a diverse group of cell-surface receptors that mediate key signaling events during animal development and are frequently activated in cancer. We show here that deletion of the extracellular regions of 10 RTKs representing 7 RTK classes or their substitution with the dimeric immunoglobulin Fc region results in constitutive receptor phosphorylation but fails to result in phosphorylation of downstream signaling effectors Erk or Akt. Conversely, substitution of RTK extracellular regions with the extracellular region of the Epidermal Growth Factor Receptor (EGFR) results in increases in effector phosphorylation in response to EGF. These results indicate that the activation signal generated by the EGFR extracellular region is capable of activating at least seven different RTK classes. Failure of phosphorylated Fc-RTK chimeras or RTKs with deleted extracellular regions to stimulate phosphorylation of downstream effectors indicates that either dimerization and receptor phosphorylation per se are insufficient to activate signaling or constitutive dimerization leads to pathway inhibition.
受体酪氨酸激酶（RTKs）是一组多样化的细胞表面受体，它们在动物发育过程中介导关键的信号事件，并且经常在癌症中被激活。我们在这里表明，删除代表 7 个 RTK 类别的 10 个 RTK 的细胞外区域或用二聚免疫球蛋白 Fc 区域替换它们，导致受体的组成性磷酸化，但不能导致下游信号效应物 Erk 或 Akt 的磷酸化。相反，用表皮生长因子受体（EGFR）的细胞外区域替换 RTK 的细胞外区域，导致对 EGF 的反应中效应物磷酸化的增加。这些结果表明，EGFR 细胞外区域产生的激活信号能够激活至少七种不同的 RTK 类。磷酸化的 Fc-RTK 嵌合体或缺少细胞外区域的 RTK 未能刺激下游效应物的磷酸化，表明二聚化和受体磷酸化本身不足以激活信号通路，或者组成性二聚化导致通路抑制。
