title: Role of GRB2-associated binder 1 in epidermal growth factor receptor-induced signaling in head and neck squamous cell carcinoma.
abstract: The epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). Despite the high expression of EGFR in HNSCC, EGFR inhibitors have only limited success as monotherapy. The Grb2-associated binder (GAB) family of adaptor proteins acts as docking/scaffolding molecules downstream of tyrosine kinase receptors. We hypothesized that GAB1 may amplify EGFR-induced signaling in HNSCCs and therefore could play a role in the reduced sensitivity of HNSCC to EGFR inhibitors. We used representative human HNSCC cell lines overexpressing wild type EGFR, and expressing GAB1 but not GAB2. We demonstrated that baseline Akt and MAPK signaling were reduced in HNSCC cells in which GAB1 expression was reduced. Furthermore, the maximal EGF-induced activation of the Akt and MAPK pathway was reduced and delayed, and the duration of the EGF-induced activation of these pathways was reduced in cells with GAB1 knock-down. In agreement with this, HNSCC cells in which GAB1 levels were reduced showed an increased sensitivity to the EGFR inhibitor gefitinib. Our work demonstrates that GAB1 plays an important role as part of the mechanism of by which EGFR induces induced activation of the MAPK and AKT pathway. Our results identify GAB1 as an amplifier of the EGFR-initiated signaling, which may also interfere with EGFR degradation. These findings support the emerging notion that reducing GAB1 function may sensitize HNSCC to EGFR inhibitors, hence representing a new therapeutic target HNSCC treatment in combination with EGFR targeting agents.
authors.affiliation: General Medical Oncology, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Hoeben
authors.forename: D
authors.initials: D
authors.lastname: Martin
authors.forename: P M
authors.initials: PM
authors.lastname: Clement
authors.forename: J
authors.initials: J
authors.lastname: Cools
authors.forename: J S
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; C490895:GAB2 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D000077156:Gefitinib