title: Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated shedding.
abstract: The ectodomain of certain transmembrane proteins can be released by the action of cell surface proteases, termed secretases. Here we have investigated how mitogen-activated protein kinases (MAPKs) control the shedding of membrane proteins. We show that extracellular signal-regulated kinase (Erk) acts as an intermediate in protein kinase C-regulated TrkA cleavage. We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (TACE) is phosphorylated by Erk at threonine 735. In addition, we show that Erk and TACE associate. This association is favored by Erk activation and by the presence of threonine 735. In contrast to the Erk route, the p38 MAPK was able to stimulate TrkA cleavage in cells devoid of TACE activity, indicating that other proteases are also involved in TrkA shedding. These results demonstrate that secretases are able to discriminate between the different stimuli that trigger membrane protein ectodomain cleavage and indicate that phosphorylation by MAPKs may regulate the proteolytic function of membrane secretases.
authors.affiliation: Instituto de Microbiología Bioquímica and Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, 37007-Salamanca, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Díaz-Rodríguez
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Montero
authors.forename: Azucena
authors.initials: A
authors.lastname: Esparís-Ogando
authors.forename: Laura
authors.initials: L
authors.lastname: Yuste
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D020917:Receptor, trkA; D015183:Restriction Mapping; D012190:Retroviridae; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013912:Threonine; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D013912:Threonine; D020917:Receptor, trkA; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D013755:Tetradecanoylphorbol Acetate