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Embryonic lethality and defective mammary gland development in activator function impaired conditional knock-in ErbB3V943R mice

ABSTRACT: ERBB3, a pseudo-kinase domain containing human epidermal growth factor receptor (ERBB/HER) family member, plays a key role in multiple cellular processes and is required for normal embryonic development. Following ligand binding, ERBB3 heterodimerizes preferentially with ERBB2, leading to allosteric kinase activation and signaling. ERBB3 has been shown to function primarily as an activator kinase that activates the receiver kinase in the asymmetric dimer activation complex. Structural studies of the activator-receiver interface have identified V943 as a key residue required for ERBB3 mediated activation of ERBB2. Here we report the generation of a knock-in mouse model where the endogenous ErbB3 allele was modified to allow tissue-specific conditional expression of ErbB3V943R (ErbB3CKI-V943R). Activation of ErbB3V943R expression during development resulted in embryonic lethality at around E12.0. Analysis of the embryos reveals thinning of the myocardium and reduced mesenchyme within the endocardial cushion of the heart, reminiscent of ErbB3 knockout mice. Tissue specific expression of ErbB3V943R in the epithelial cells of the mammary gland using an MMTV-Cre driver results in delayed elongation of the ductal network during puberty. Consistent with this, single cell RNA-seq analysis showed a reduction in a specific subset of fibrinogen-producing luminal epithelial cells. Our studies establish the importance in vivo of the allosteric interface in activation of the ERBB family and also provides an important tool that can be used to understand the role of ERBB3 in cancer development.

ORGANISM(S): Mus musculus

PROVIDER: GSE146437 | GEO | 2020/11/13

REPOSITORIES: GEO

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Project description:This model is from the article: A multiscale modeling approach to investigate molecular mechanisms of pseudokinase activation and drug resistance in the HER3/ErbB3 receptor tyrosine kinase signaling network. Telesco SE, Shih AJ, Jia F, Radhakrishnan R. Mol Biosyst. 2011 Jun;7(6):2066-80. 21509365 , Abstract: Multiscale modeling provides a powerful and quantitative platform for investigating the complexity inherent in intracellular signaling pathways and rationalizing the effects of molecular perturbations on downstream signaling events and ultimately, on the cell phenotype. Here we describe the application of a multiscale modeling scheme to the HER3/ErbB3 receptor tyrosine kinase (RTK) signaling network, which regulates critical cellular processes including proliferation, migration and differentiation. The HER3 kinase is a topic of current interest and investigation, as it has been implicated in mechanisms of resistance to tyrosine kinase inhibition (TKI) of EGFR and HER2 in the treatment of many human malignancies. Moreover, the commonly regarded status of HER3 as a catalytically inactive 'pseudokinase' has recently been challenged by our previous study, which demonstrated robust residual kinase activity for HER3. Through our multiscale model, we investigate the most significant molecular interactions that contribute to potential mechanisms of HER3 activity and the physiological relevance of this activity to mechanisms of drug resistance in an ErbB-driven tumor cell in silico. The results of our molecular-scale simulations support the characterization of HER3 as a weakly active kinase that, in contrast to its fully-active ErbB family members, depends upon a unique hydrophobic interface to coordinate the alignment of specific catalytic residues required for its activity. Translating our molecular simulation results of the uniquely active behavior of the HER3 kinase into a physiologically relevant environment, our HER3 signaling model demonstrates that even a weak level of HER3 activity may be sufficient to induce AKT signaling and TKI resistance in the context of an ErbB signaling-dependent tumor cell, and therefore therapeutic targeting of HER3 may represent a superior treatment strategy for specific ErbB-driven cancers. Note: This model is an extension of the model published by Schoeberl et al., 2009 [PMID:19567914] . This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal of human cancers underscoring the need to identify new therapeutic vulnerabilities. Previously, we reported high expression of transcriptional co-regulators C-terminal binding proteins (CtBP) 1 and 2 in human PDAC, however their precise role in PDAC formation or progression remains unclear. Here, we have studied PDAC tumor dependency on CtBPs for growth and metastasis using an orthotopic syngeneic pancreatic tumor mouse model. CRISPR-based homozygous deletion of Ctbp2 dramatically decreased PDAC tumor growth, drastically reduced metastatic potential, and significantly prolonged survival. Interrogating differential gene expression of the orthotopic PDAC tumors from CtBP2 WT vs. CtBP2 KO cohorts, we identified significant downregulation of the EGFR-superfamily receptor ErbB3 in CtBP2 KO tumors, and further determined that CtBP regulates expression of both the ErbB2 and 3 EGFR superfamily genes in PDAC cells. We therefore hypothesized that CtBP regulation of physiologic ErbB2/3 signaling contributes, in part, to PDAC growth and metastasis. Indeed, we observed that CtBP2 KO cells exhibited severely attenuated activation of phospho-Akt after neuregulin stimulation of ErbB2/3, and we demonstrate that human PDAC cells also show CtBP dependence of ErbB2/3 expression. Our results suggest that a subset of PDAC tumors is dependent on physiologic ErbB2/3 signaling and could be targeted by pharmacologic inhibitors of ErbB2 and/or ErbB3. Providing proof of concept, the ErbB2-targeted multikinase inhibitor lapatinib, but not the ErbB1/EGFR targeted agent erlotinib, effectively killed ErbB3 expressing PDAC cells, while CtBP2 KO cells where ErbB3 expression was extinguished, were resistant to lapatinib. Taken together, our data suggests that ErBb2/3 targeted therapeutics can effectively target a critical PDAC dependency on physiologic ErbB2/3 signaling which is the result of CtBP’s oncogenic transcriptional program that drives PDAC tumor progression.

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Embryonic lethality and defective mammary gland development in activator function impaired conditional knock-in ErbB3V943R mice

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