title: Orchestration of ErbB3 signaling through heterointeractions and homointeractions.
abstract: Members of the ErbB family of receptor tyrosine kinases are capable of both homointeractions and heterointeractions. Because each receptor has a unique set of binding sites for downstream signaling partners and differential catalytic activity, subtle shifts in their combinatorial interplay may have a large effect on signaling outcomes. The overexpression and mutation of ErbB family members are common in numerous human cancers and shift the balance of activation within the signaling network. Here we report the development of a spatial stochastic model that addresses the dynamics of ErbB3 homodimerization and heterodimerization with ErbB2. The model is based on experimental measures for diffusion, dimer off-rates, kinase activity, and dephosphorylation. We also report computational analysis of ErbB3 mutations, generating the prediction that activating mutations in the intracellular and extracellular domains may be subdivided into classes with distinct underlying mechanisms. We show experimental evidence for an ErbB3 gain-of-function point mutation located in the C-lobe asymmetric dimerization interface, which shows enhanced phosphorylation at low ligand dose associated with increased kinase activity.
authors.affiliation: Department of Chemical and Biological Engineering, University of New Mexico, Albuquerque, NM 87131 Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM 87545.
authors.forename: Meghan
authors.initials: M
authors.lastname: McCabe Pryor
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, NM 87131 Cancer Center, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Mara P
authors.initials: MP
authors.lastname: Steinkamp
authors.affiliation: Department of Mathematics, West Virginia University, Morgantown, WV 25606.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Halasz
authors.affiliation: Department of Mathematics, West Virginia University, Morgantown, WV 25606.
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of OB/GYN, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
authors.forename: Shujie
authors.initials: S
authors.lastname: Yang
authors.affiliation: Viracor-IBT Laboratories, Lee's Summit, MO 64086.
authors.forename: Marilyn S
authors.initials: MS
authors.lastname: Smith
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Gergely
authors.initials: G
authors.lastname: Zahoransky-Kohalmi
authors.affiliation: Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Mark
authors.initials: M
authors.lastname: Swift
authors.affiliation: Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Xu
authors.affiliation: Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Dorit
authors.initials: D
authors.lastname: Hanein
authors.affiliation: Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Niels
authors.initials: N
authors.lastname: Volkmann
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, NM 87131 Cancer Center, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Diane S
authors.initials: DS
authors.lastname: Lidke
authors.affiliation: Department of Chemical and Biological Engineering, University of New Mexico, Albuquerque, NM 87131 Cancer Center, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM 87131 Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Edwards
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, NM 87131 Cancer Center, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM 87131 bwilson@salud.unm.edu.
authors.forename: Bridget S
authors.initials: BS
authors.lastname: Wilson
mesh_terms: D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008024:Ligands; C581292:ERBB3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D020893:Receptor, ErbB-3