Conserved Roles for Receptor Tyrosine Kinase Extracellular Regions in Regulating Receptor and Pathway Activity

Abstract

SummaryReceptor 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 phosphorylationper seare insufficient to activate signaling or constitutive dimerization leads to pathway inhibition.