title: Protein kinase D2 regulates chromogranin A secretion in human BON neuroendocrine tumour cells.
abstract: Chromogranin A is a member of the granin family of acidic secretory glycoproteins that is found in secretory granules of many endocrine cells including neuroendocrine tumour cells. This hormone serves as a model system for autonomous hormone secretion by the so called functional neuroendocrine tumours of the gastrointestinal tract. The precise regulation of chromogranin secretion at the level of the Golgi apparatus is a subject of intense research. The protein kinase D (PKD) family of serine threonine kinases has so far been implicated in the regulation of constitutive secretion in epithelial cells. Here we examined whether PKD2 expression and activity could also play a role in the release of secretory granules from the trans Golgi network (TGN) in neuroendocrine tumour cells and hence be a target to block autonomous secretion by these tumours. Our data show that expression and catalytic activity of PKD2 are required for the release of chromogranin A containing secretory vesicles. Inhibition of PKD2 activity or siRNA knockdown of PKD2 resulted in a marked perinuclear retention of chromogranin A immunofluorescence in the trans Golgi network and led to a marked reduction in basal as well as phorbol ester stimulated secretion of chromogranin A into the supernatant of cells. Thus, PKD2 controls the release of secretory granules in neuroendocrine tumour cells at the level of the Golgi apparatus and could hence serve as a novel target to block hormone secretion in functional neuroendocrine tumours.
authors.affiliation: Department of Internal Medicine I, University of Ulm, D-89081 Ulm, Germany.
authors.forename: Götz
authors.initials: G
authors.lastname: von Wichert
authors.forename: Teresa
authors.initials: T
authors.lastname: Edenfeld
authors.forename: Julia
authors.initials: J
authors.lastname: von Blume
authors.forename: Holger
authors.initials: H
authors.lastname: Krisp
authors.forename: Denis
authors.initials: D
authors.lastname: Krndija
authors.forename: Heidrun
authors.initials: H
authors.lastname: Schmid
authors.forename: Franz
authors.initials: F
authors.lastname: Oswald
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lother
authors.forename: Paul
authors.initials: P
authors.lastname: Walther
authors.forename: Guido
authors.initials: G
authors.lastname: Adler
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001693:Biological Transport, Active; D045744:Cell Line, Tumor; D053379:Chromogranin A / Q000378:metabolism*; D006056:Golgi Apparatus / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D018358:Neuroendocrine Tumors / Q000201:enzymology* / Q000378:metabolism*; D000091283:Protein Kinase D2; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D022142:Secretory Vesicles / Q000502:physiology; D015398:Signal Transduction; D021601:trans-Golgi Network / Q000502:physiology
chemical_list: C506150:CHGA protein, human; D053379:Chromogranin A; D000091283:Protein Kinase D2; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011494:Protein Kinases