title: Integration of Golgi trafficking and growth factor signaling by the lipid phosphatase SAC1.
abstract: When a growing cell expands, lipids and proteins must be delivered to its periphery. Although this phenomenon has been observed for decades, it remains unknown how the secretory pathway responds to growth signaling. We demonstrate that control of Golgi phosphatidylinositol-4-phosphate (PI(4)P) is required for growth-dependent secretion. The phosphoinositide phosphatase SAC1 accumulates at the Golgi in quiescent cells and down-regulates anterograde trafficking by depleting Golgi PI(4)P. Golgi localization requires oligomerization of SAC1 and recruitment of the coat protein (COP) II complex. When quiescent cells are stimulated by mitogens, SAC1 rapidly shuttles back to the endoplasmic reticulum (ER), thus releasing the brake on Golgi secretion. The p38 mitogen-activated kinase (MAPK) pathway induces dissociation of SAC1 oligomers after mitogen stimulation, which triggers COP-I-mediated retrieval of SAC1 to the ER. Inhibition of p38 MAPK abolishes growth factor-induced Golgi-to-ER shuttling of SAC1 and slows secretion. These results suggest direct roles for p38 MAPK and SAC1 in transmitting growth signals to the secretory machinery.
authors.affiliation: Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, OR 97239.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Blagoveshchenskaya
authors.forename: Fei Ying
authors.initials: FY
authors.lastname: Cheong
authors.forename: Holger M
authors.initials: HM
authors.lastname: Rohde
authors.forename: Greta
authors.initials: G
authors.lastname: Glover
authors.forename: Andreas
authors.initials: A
authors.lastname: Knödler
authors.forename: Teresa
authors.initials: T
authors.lastname: Nicolson
authors.forename: Guido
authors.initials: G
authors.lastname: Boehmelt
authors.forename: Peter
authors.initials: P
authors.lastname: Mayinger
mesh_terms: D000818:Animals; D022181:COP-Coated Vesicles / Q000378:metabolism / Q000648:ultrastructure; D019556:COS Cells; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006056:Golgi Apparatus / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D041681:NIH 3T3 Cells; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008934:Mitogens; D018129:Phosphatidylinositol Phosphates; C416669:Sac1 protein, mammalian; C037178:phosphatidylinositol 4-phosphate; D048051:p38 Mitogen-Activated Protein Kinases