Kinase Receiver-Activator Preference in ErbB Heterodimers Determined by Intracellular Regions and not Coupled to Extracellular Asymmetry [Signal Transduction]

December 2nd, 2014 by Ward, M. D., Leahy, D. J.

The Epidermal Growth Factor Receptor (EGFR) family comprises four homologs in humans collectively known as the ErbBs or HERs. ErbBs are receptor tyrosine kinases that become activated when ligands bind to their extracellular regions and promote formation of specific homo- and heterodimers with enhanced tyrosine kinase activity. An essential feature of ErbB activation is formation of an asymmetric kinase dimer in which the C-lobe of one kinase serves as the activator or donor kinase by binding the N-lobe of a receiver or acceptor kinase and stabilizing its active conformation. ErbB extracellular regions are also thought to form active, asymmetric dimers in which only one subunit binds ligand. The observation that the unliganded ErbB2 kinase preferentially serves as the activator kinase when paired with EGFR/ErbB1 implied that extracellular asymmetry in ErbBs might be coupled to intracellular asymmetry with unliganded partners favoring the activator kinase position. Using cell based stimulation assays and chimeric ErbBs, we show that extracellular asymmetry is not coupled to intracellular asymmetry and ErbB intracellular regions are sufficient to determine relative kinase activator-receiver orientation. We further show a hierarchy of activator-receiver preferences among ErbBs with EGFR/ErbB1 the strongest receiver followed by ErbB2 and then ErbB4 and that cis phosphorylation of EGFR and ErbB2 appears to be negligible. This hierarchy shapes the nature of signaling responses to different ligands in cells expressing multiple ErbBs.
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