The Coffin-Lowry syndrome-associated protein RSK2 is implicated in calcium-regulated exocytosis through the regulation of PLD1.
Exocytosis of neurotransmitters and hormones occurs through the fusion of secretory vesicles with the plasma membrane. This highly regulated process involves key proteins, such as SNAREs, and specific lipids at the site of membrane fusion. Phospholipase D (PLD) has recently emerged as a promoter of membrane fusion in various exocytotic events potentially by providing fusogenic cone-shaped phosphatidic acid. We show here that PLD1 is regulated by ribosomal S6 kinase 2 (RSK2)-dependent phosphorylation. RSK2 is activated by a high K(+)-induced rise in cytosolic calcium. Expression of inactive RSK2 mutants or selective knockdown of endogenous RSK2 dramatically affects the different kinetic components of the exocytotic response in chromaffin cells. RSK2 physically interacts with and stimulates PLD activity through the phosphorylation of Thr-147 in the PLD1 amino-terminal phox homology domain. Expression of PLD1 phosphomimetic mutants fully restores secretion in cells depleted of RSK2, suggesting that RSK2 is a critical upstream signaling element in the activation of PLD1 to produce the lipids required for exocytosis. We propose that PLD-related defects in neuronal and endocrine activities could contribute to the effect observed after the loss-of-function mutations in Rsk2 that lead to Coffin-Lowry syndrome, an X-linked form of growth and mental retardation.
Département Neurotransmission et Sécrétion Neuroendocrine, Institut des Neurosciences Cellulaires et Intégratives, Unité Mixte de Recherche 7168/LC2, Centre National de la Recherche Scientifique, Université Louis Pasteur, Strasbourg, France.
Maria
M
Zeniou-Meyer
Yuanyuan
Y
Liu
Aurélie
A
Béglé
Mary E
ME
Olanich
Mary
M
Olanish
André
A
Hanauer
Ute
U
Becherer
Jens
J
Rettig
Marie-France
MF
Bader
Nicolas
N
Vitale
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D019439:Chromaffin Cells / Q000201:enzymology / Q000378:metabolism*; D038921:Coffin-Lowry Syndrome / Q000201:enzymology* / Q000235:genetics; D005089:Exocytosis / Q000235:genetics; D016716:PC12 Cells; D010712:Phosphatidic Acids / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*
D010712:Phosphatidic Acids; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D010739:Phospholipase D; C106801:phospholipase D1; D002118:Calcium