title: Cross-talk with Ca(2+) influx does not underlie the role of extracellular signal-regulated kinases in cytotoxic T lymphocyte lytic granule exocytosis.
abstract: One important mechanism cytotoxic T lymphocytes use to kill target cells is exocytosis of lytic granules that contain cytotoxic agents such as perforin and granzyme. Ca(2+) influx and activation of protein kinase C have been known for many years to be key signals for granule exocytosis. Recent work has suggested that activation of extracellular signal-regulated kinases (ERK), members of the mitogen-activated protein kinase (MAP kinase) family, may be a third required signal. We surmised that the involvement of ERK in lytic granule exocytosis could be mediated through cross-talk with Ca(2+) influx, rather than constituting an independent signal. We tested this idea using TALL-104 human leukemic CTLs as a model system and discovered the following. 1) ERK inhibition caused a modest decrease in the amplitude of increases in intracellular Ca(2+) concentration, but this effect cannot account for the profound inhibition of granule exocytosis. 2) Ca(2+) influx can activate ERK in TALL-104 cells, but this effect does not contribute to ERK activation stimulated by solid phase anti-CD3 monoclonal antibodies. We conclude that cross-talk between ERK signaling and Ca(2+) does not mediate the role of ERK in CTL lytic granule exocytosis.
authors.affiliation: Department of Physiology and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
authors.forename: Allan F
authors.initials: AF
authors.lastname: Fierro
authors.forename: Georjeana A
authors.initials: GA
authors.lastname: Wurth
authors.forename: Adam
authors.initials: A
authors.lastname: Zweifach
mesh_terms: D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D003594:Cytoplasmic Granules / Q000378:metabolism*; D004789:Enzyme Activation; D005089:Exocytosis; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D051966:Phospholipase C gamma; D011493:Protein Kinase C / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D010738:Type C Phospholipases / Q000502:physiology
chemical_list: D005419:Flavonoids; D011948:Receptors, Antigen, T-Cell; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium