title: Regulation of the ErbB network by the MIG6 feedback loop in physiology, tumor suppression and responses to oncogene-targeted therapeutics.
abstract: The ErbB signaling network instructs the execution of key cellular programs, such as cell survival, proliferation and motility, through the generation of robust signals of defined strength and duration. In contrast, unabated ErbB signaling disrupts tissue homeostasis and leads to cell transformation. Cells oppose the threat inherent in excessive ErbB activity through several mechanisms of negative feedback regulation. Inducible feedback inhibitors (IFIs) are expressed in the context of transcriptional responses triggered by ErbB signaling, thus being uniquely suited to regulate ErbB activity during the execution of complex cellular programs. This review focuses on MIG6, an IFI that restrains ErbB signaling by mediating ErbB kinase suppression and receptor down-regulation. We will review key issues in MIG6 function, regulation and tumor suppressor activity. Subsequently, the role for MIG6 loss in the pathogenesis of tumors driven by ErbB oncogenes as well as in the generation of cellular addiction to ErbB signaling will be discussed. We will conclude by analyzing feedback inhibition by MIG6 in the context of therapies directed against ErbB and non-ErbB oncogenes.
authors.affiliation: Laboratory of Cell Signaling, Regina Elena National Cancer Institute, via E. Chianesi, 53, 00144 Rome, Italy. Electronic address: anastasi@ifo.it.
authors.forename: Sergio
authors.initials: S
authors.lastname: Anastasi
authors.affiliation: Laboratory of Cell Signaling, Regina Elena National Cancer Institute, via E. Chianesi, 53, 00144 Rome, Italy. Electronic address: lamberti@ifo.it.
authors.forename: Dante
authors.initials: D
authors.lastname: Lamberti
authors.affiliation: Institute of Cell Biology and Neurobiology, CNR, 00016 Monterotondo, Italy. Electronic address: alema@ibc.cnr.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Alemà
authors.affiliation: Laboratory of Cell Signaling, Regina Elena National Cancer Institute, via E. Chianesi, 53, 00144 Rome, Italy. Electronic address: segatto@ifo.it.
authors.forename: Oreste
authors.initials: O
authors.lastname: Segatto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D066246:ErbB Receptors / Q000378:metabolism*; D025461:Feedback, Physiological; D006801:Humans; D058990:Molecular Targeted Therapy; D009857:Oncogenes; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors
keywords: ErbB receptors; Feedback inhibition; MIG6; Targeted cancer therapeutics; Tumor suppression