title: c-Src/Cav1-dependent activation of the EGFR by Dsg2.
abstract: The desmosomal cadherin, desmoglein 2 (Dsg2), is deregulated in a variety of human cancers including those of the skin. When ectopically expressed in the epidermis of transgenic mice, Dsg2 activates multiple mitogenic signaling pathways and increases susceptibility to tumorigenesis. However, the molecular mechanism responsible for Dsg2-mediated cellular signaling is poorly understood. Here we show overexpression as well as co-localization of Dsg2 and EGFR in cutaneous SCCs in vivo. Using HaCaT keratinocytes, knockdown of Dsg2 decreases EGFR expression and abrogates the activation of EGFR, c-Src and Stat3, but not Erk1/2 or Akt, in response to EGF ligand stimulation. To determine whether Dsg2 mediates signaling through lipid microdomains, sucrose density fractionation illustrated that Dsg2 is recruited to and displaces Cav1, EGFR and c-Src from light density lipid raft fractions. STED imaging confirmed that the presence of Dsg2 disperses Cav1 from the cell-cell borders. Perturbation of lipid rafts with the cholesterol-chelating agent MβCD also shifts Cav1, c-Src and EGFR out of the rafts and activates signaling pathways. Functionally, overexpression of Dsg2 in human SCC A431 cells enhances EGFR activation and increases cell proliferation and migration through a c-Src and EGFR dependent manner. In summary, our data suggest that Dsg2 stimulates cell growth and migration by positively regulating EGFR level and signaling through a c-Src and Cav1-dependent mechanism using lipid rafts as signal modulatory platforms.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Overmiller
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Kathleen P
authors.initials: KP
authors.lastname: McGuinn
authors.affiliation: Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE, USA.
authors.forename: Brett J
authors.initials: BJ
authors.lastname: Roberts
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Felicia
authors.initials: F
authors.lastname: Cooper
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.|Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Brennan-Crispi
authors.affiliation: Laboratory of Biophysics, Department of Cell Biology and Anatomy, University of Turku, Turku, Finland.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Deguchi
authors.affiliation: Department of Dermatology, University of Turku and Turku Hospital, Turku, Finland.
authors.forename: Sirkku
authors.initials: S
authors.lastname: Peltonen
authors.affiliation: Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE, USA.
authors.forename: James K
authors.initials: JK
authors.lastname: Wahl
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.|Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Mỹ G
authors.initials: MG
authors.lastname: Mahoney
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D051301:Desmoglein 2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D021962:Membrane Microdomains / Q000201:enzymology / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; C495314:DSG2 protein, human; D051301:Desmoglein 2; C512478:EGFR protein, human; D066246:ErbB Receptors; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human
keywords: EGFR; Stat3; c-Src; caveolin-1; desmoglein-2