title: Dissociation of epidermal growth factor receptor and ErbB2 heterodimers in the presence of somatostatin receptor 5 modulate signaling pathways.
abstract: Epidermal growth factor through the stimulation of epidermal growth factor receptor (EGFR) plays a critical role in the activation of MAPKs and phosphatidylinositol-3-protein kinase/AKT cell survival pathways attributed in many pathological conditions. At the cellular level, such functions involve EGFR overactivation and phosphorylation. In the present study, we describe that human embryonic kidney-293 cells transfected with somatostatin (SST) receptor 5 (SSTR5) exhibit inhibition of EGFR phosphorylation and modulate MAPK and phosphatidylinositol-3-protein kinase/AKT cell survival signaling. Furthermore, suppression of EGFR by using small interference RNA and an antagonist (AG1478) potentiates the SST effect via activation of SSTR5 on signaling molecules. In wild-type human embryonic kidney-293 cells, EGFR/ErbB2 exists as constitutive heterodimers. The presence of SSTR5 leads to the dissociation of the heteromeric complex of EGFR/ErbB2 and display preferential heterodimerization between SSTR5 and EGFR in an agonist-dependent manner. These findings highlight a new undiscovered mechanism and potential role of SSTR5 to attenuate the EGFR-mediated signaling pathways involved in tumorigenesis. Our data indicate that the activation and/or overexpression of SST receptors along with the inhibition of EGFR will serve as an important therapeutic approach in the treatment of ErbB-positive tumors.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Kharmate
authors.forename: Padmesh S
authors.initials: PS
authors.lastname: Rajput
authors.forename: Heather L
authors.initials: HL
authors.lastname: Watt
authors.forename: Rishi K
authors.initials: RK
authors.lastname: Somvanshi
authors.forename: Nicole
authors.initials: N
authors.lastname: Chaudhari
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Qiu
authors.forename: Ujendra
authors.initials: U
authors.lastname: Kumar
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D017481:Receptors, Somatostatin; C094573:somatostatin receptor 5; C508053:ERBB2 protein, human