title: Molecular modeling of ErbB4/HER4 kinase in the context of the HER4 signaling network helps rationalize the effects of clinically identified HER4 somatic mutations on the cell phenotype.
abstract: In the ErbB/HER family of receptor tyrosine kinases, the deregulation of the EGFR/ErbB1/HER1, HER2/ErbB2, and HER3/ErbB3 kinases is associated with several cancers, while the HER4/ErbB4 kinase has been shown to play an anti-carcinogenic role in certain tumors. We present molecular and network models of HER4/ErbB4 activation and signaling in order to elucidate molecular mechanisms of activation and rationalize the effects of the clinically identified HER4 somatic mutants. Our molecular-scale simulations identify the important role played by the interactions within the juxtamembrane region during the activation process. Our results also support the hypothesis that the HER4 mutants may heterodimerize but not activate, resulting in blockage of the HER4-STAT5 differentiation pathway, in favor of the proliferative PI3K/AKT pathway. Translating our molecular simulation results into a cellular pathway model of wild type versus mutant HER4 signaling, we are able to recapitulate the major features of the PI3K/AKT and JAK/STAT activation downstream of HER4. Our model predicts that the signaling downstream of the wild type HER4 is enriched for the JAK-STAT pathway, whereas downstream of the mutant HER4 is enriched for the PI3K/AKT pathway. HER4 mutations may hence constitute a cellular shift from a program of differentiation to that of proliferation.
authors: University of Pennsylvania, Department of Bioengineering, Philadelphia, PA, USA.
authors: Shannon E
authors: SE
authors: Telesco
authors: Rajanikanth
authors: R
authors: Vadigepalli
authors: Ravi
authors: R
authors: Radhakrishnan
mesh_terms: D019295:Computational Biology / Q000379:methods*; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D056004:Molecular Dynamics Simulation; D009154:Mutation; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology*
chemical_list: D021122:Protein Subunits; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4
keywords: Cellular signaling pathways; Molecular dynamics; Network modeling; Receptor tyrosine kinase; Structural biology