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Conserved Roles for Receptor Tyrosine Kinase Extracellular Regions in Regulating Receptor and Pathway Activity
bioRxiv - Molecular Biology Pub Date : 2020-05-31 , DOI: 10.1101/2020.05.29.122135
Monica Gonzalez-Magaldi , Jacqueline M. McCabe , Haley N. Cartwright , Ningze Sun , Daniel J. Leahy

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. Ligand-induced dimerization is the canonical mechanism by which RTKs are thought to be activated. 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 Erk and/or Akt phosphorylation in response to EGF. These results indicate that the activation signal generated by the EGFR extracellular region is capable of activating at least 7 different RTK classes. Failure of phosphorylated Fc-RTK chimeras 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.

中文翻译:

受体酪氨酸激酶胞外区在调节受体和通路活性中的保守作用

受体酪氨酸激酶(RTK)包含多种细胞表面受体,它们在动物发育过程中介导关键的信号传导事件,并经常在癌症中被激活。配体诱导的二聚化是RTK被认为被激活的典型机制。我们在这里显示,代表7个RTK类的10个RTK的胞外区域的缺失或被二聚体免疫球蛋白Fc区取代会导致组成型受体磷酸化,但不会导致下游信号传导效应子Erk或Akt的磷酸化。相反,用表皮生长因子受体(EGFR)的胞外区替代RTK胞外区会导致Erk响应中Erk和/或Akt磷酸化增加。这些结果表明,由EGFR细胞外区域产生的激活信号能够激活至少7种不同的RTK类别。磷酸化的Fc-RTK嵌合体未能刺激下游效应子的磷酸化,表明二聚化和受体磷酸化本身不足以激活信号传导或组成性二聚化导致途径抑制。
更新日期:2020-05-31
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