Journal article
Orchestration of ErbB3 signaling through heterointeractions and homointeractions
Molecular biology of the cell, Vol.26(22), pp.4109-4123
11/05/2015
DOI: 10.1091/mbc.E14-06-1114
PMCID: PMC4710241
PMID: 26378253
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.
Details
- Title: Subtitle
- Orchestration of ErbB3 signaling through heterointeractions and homointeractions
- Creators
- Meghan McCabe Pryor - Department of Chemical and Biological Engineering, University of New Mexico, Albuquerque, NM 87131 Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM 87545Mara P Steinkamp - 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 87131Adam M Halasz - Department of Mathematics, West Virginia University, Morgantown, WV 25606Ye Chen - Department of Mathematics, West Virginia University, Morgantown, WV 25606Shujie Yang - Department of OB/GYN, University of Iowa Carver College of Medicine, Iowa City, IA 52242Marilyn S Smith - Viracor-IBT Laboratories, Lee's Summit, MO 64086Gergely Zahoransky-Kohalmi - Department of Pathology, University of New Mexico, Albuquerque, NM 87131Mark Swift - Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037Xiao-Ping Xu - Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037Dorit Hanein - Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037Niels Volkmann - Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037Diane S Lidke - 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 87131Jeremy S Edwards - 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 87131Bridget S Wilson - 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
- Resource Type
- Journal article
- Publication Details
- Molecular biology of the cell, Vol.26(22), pp.4109-4123
- DOI
- 10.1091/mbc.E14-06-1114
- PMID
- 26378253
- PMCID
- PMC4710241
- NLM abbreviation
- Mol Biol Cell
- ISSN
- 1059-1524
- eISSN
- 1939-4586
- Publisher
- American Society for Cell Biology; United States
- Grant note
- P30 CA118100 / NCI NIH HHS P50 GM085273 / NIGMS NIH HHS R01 GM104973 / NIGMS NIH HHS R01 CA119232 / NCI NIH HHS K25CA131558 / NCI NIH HHS K25 CA131558 / NCI NIH HHS P30CA118100 / NCI NIH HHS P50GM085273 / NIGMS NIH HHS R01GM104973 / NIGMS NIH HHS CA119232 / NCI NIH HHS
- Language
- English
- Date published
- 11/05/2015
- Academic Unit
- Pathology
- Record Identifier
- 9984047717302771
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