title: c-Src mediated tyrosine phosphorylation of plakophilin 3 as a new mechanism to control desmosome composition in cells exposed to oxidative stress.
abstract: Plakophilins (PKP1 to PKP3) are essential for the structure and function of desmosomal junctions as demonstrated by the severe skin defects observed as a result of loss-of-function mutations in mice and men. PKPs play additional roles in cell signaling processes, such as those controlling the cellular stress response and cell proliferation. A key post-translational process controlling PKP function is phosphorylation. We have discovered that reactive oxygen species (ROS) trigger the c-Src kinase-mediated tyrosine (Tyr)-195 phosphorylation of PKP3. This modification is associated with a change in the subcellular distribution of the protein. Specifically, PKP3 bearing phospho-Tyr-195 is released from the desmosomes, suggesting that phospho-Tyr-195 is relevant for the control of desmosome disassembly and function, at least in cells exposed to ROS. Tyr-195 phosphorylation is transient under normal physiological conditions and seems to be strictly regulated, as the activation of particular growth factor receptors results in a modification at this site only when tyrosine phosphatases are inactivated by pervanadate. We have identified Tyr-195 of PKP3 as a phosphorylation target of epidermal growth factor receptor signaling. Interestingly, this PKP3 phosphorylation also occurs in certain poorly differentiated adenocarcinomas of the prostate, suggesting a possible role in tumor progression. Our study thus identifies a new mechanism controlling PKP3 and hence desmosome function in epithelial cells.
authors.affiliation: Institute of Pathology, Philipps University of Marburg, Baldingerstrasse, 35033, Marburg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Neuber
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jäger
authors.forename: Merle
authors.initials: M
authors.lastname: Meyer
authors.forename: Viktoria
authors.initials: V
authors.lastname: Wischmann
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Koch
authors.forename: Roland
authors.initials: R
authors.lastname: Moll
authors.forename: Ansgar
authors.initials: A
authors.lastname: Schmidt
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D003896:Desmosomes / Q000187:drug effects / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D017830:Octoxynol / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D051191:Plakophilins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D051191:Plakophilins; D034741:RNA, Small Interfering; D019000:Phosphotyrosine; D017830:Octoxynol; D006861:Hydrogen Peroxide; D066246:ErbB Receptors; D016392:Proto-Oncogene Proteins pp60(c-src); D010749:Phosphoprotein Phosphatases