Orchestration of erbB3 signaling through homo-dimerization and hetero-dimerization with erbB2

Orchestration of erbB3 signaling through homo-dimerization and hetero-dimerization with erbB2

Meghan McCabe Pryor,^a Mara P. Steinkampb,^c , Adam M. Halasz,^d Ye Chend, Shujie Yang,^e Marilyn S. Smith,^f Diane S. Lidke,^b,c Jeremy S. Edwardsa,^{c,g^} and Bridget S. Wilson^{b,c^}

^a Dept. of Chemical Engineering, University of New Mexico, Albuquerque, New Mexico ^b Dept. of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico ^c Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico ^d Dept. of Mathematics, West Virginia University, Morgantown, West Virginia, ^e Dept. of OB/GYN, University of Iowa Carver College of Medicine, Iowa City, Iowa ^f Viracor-IBT Laboratories, Lee's Summit, Missouri ^g Dept. of Chemistry & Chemical Biology, University of New Mexico, Albuquerque, New Mexico

ErbB receptor tyrosine kinases are capable of both homo- and hetero-dimerization. Since individual erbB family members have a unique set of binding sites for downstream signaling partners and differential catalytic activity, their combinatorial interplay is predicted to impact signaling outcomes. In human cancers, erbB family members are often overexpressed due to gene amplification or undergo activating mutations. We developed a spatial stochastic model that addresses the impact of varying ligand concentrations and erbB2-erbB3 ratios on erbB3 homo and hetero-interaction dynamics and phosphorylation state. The model also predicts the influence of several erbB3 mutation classes on phosphorylation kinetics, with specific emphasis on an erbB3 gain-of-function mutation located in the C-lobe asymmetric dimerization interface.