Orchestration of ErbB3 signaling through heterointeractions and homointeractions

Meghan Mc Cabe Pryor, Mara P. Steinkamp, Adam M. Halasz, Ye Chen, Shujie Yang, Marilyn S. Smith, Gergely Zahoransky-Kohalmi, Mark Swift, Xiao Ping Xu, Dorit Hanien, Niels Volkmann, Diane S. Lidke, Jeremy S. Edwards, Bridget S. Wilson

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4109-4123
Number of pages15
JournalMolecular Biology of the Cell
Volume26
Issue number22
DOIs
StatePublished - Nov 5 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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