Receptor Tyrosine Kinases Require a Signal in Addition to Dimerization to Trigger Pathway Activation
44 Pages Posted: 9 Jan 2020 Sneak Peek Status: Review CompleteMore...
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, but we show here that substitution of the extracellular regions of 10 RTKs representing 7 RTK classes 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 results in robust Erk and/or Akt phosphorylation in response to Epidermal Growth Factor. These results indicate that ligand-bound RTK extracellular regions provide a signal in addition to dimerization that is necessary to couple receptor phosphorylation to activation of downstream effectors and that this signal is a shared feature of at least 7 different RTK classes.
Keywords: Receptor Tyrosine Kinase, EGFR, signaling, ERK, AKT, multimerization, dimerization
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