title: A direct role for ATP1A1 in unconventional secretion of fibroblast growth factor 2.
abstract: Previous studies proposed a role for the Na/K-ATPase in unconventional secretion of fibroblast growth factor 2 (FGF2). This conclusion was based upon pharmacological inhibition of FGF2 secretion in the presence of ouabain. However, neither independent experimental evidence nor a potential mechanism was provided. Based upon an unbiased RNAi screen, we now report the identification of ATP1A1, the α1-chain of the Na/K-ATPase, as a factor required for efficient secretion of FGF2. As opposed to ATP1A1, down-regulation of the β1- and β3-chains (ATP1B1 and ATP1B3) of the Na/K-ATPase did not affect FGF2 secretion, suggesting that they are dispensable for this process. These findings indicate that it is not the membrane potential-generating function of the Na/K-ATPase complex but rather a so far unidentified role of potentially unassembled α1-chains that is critical for unconventional secretion of FGF2. Consistently, in the absence of β-chains, we found a direct interaction between the cytoplasmic domain of ATP1A1 and FGF2 with submicromolar affinity. Based upon these observations, we propose that ATP1A1 is a recruitment factor for FGF2 at the inner leaflet of plasma membranes that may control phosphatidylinositol 4,5-bisphosphate-dependent membrane translocation as part of the unconventional secretory pathway of FGF2.
authors.affiliation: From the Heidelberg University Biochemistry Center (BZH), Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Zacherl
authors.affiliation: From the Heidelberg University Biochemistry Center (BZH), Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: La Venuta
authors.affiliation: From the Heidelberg University Biochemistry Center (BZH), Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Müller
authors.affiliation: From the Heidelberg University Biochemistry Center (BZH), Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Wegehingel
authors.affiliation: From the Heidelberg University Biochemistry Center (BZH), Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
authors.forename: Eleni
authors.initials: E
authors.lastname: Dimou
authors.affiliation: the European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany, and.
authors.forename: Peter
authors.initials: P
authors.lastname: Sehr
authors.affiliation: the European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany, and.
authors.forename: Joe D
authors.initials: JD
authors.lastname: Lewis
authors.affiliation: BioQuant, Heidelberg University, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Erfle
authors.affiliation: the European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany, and.
authors.forename: Rainer
authors.initials: R
authors.lastname: Pepperkok
authors.affiliation: From the Heidelberg University Biochemistry Center (BZH), Im Neuenheimer Feld 328, 69120 Heidelberg, Germany, walter.nickel@bzh.uni-heidelberg.de.
authors.forename: Walter
authors.initials: W
authors.lastname: Nickel
mesh_terms: D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D055571:Secretory Pathway; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C503551:ATP1B1 protein, human; C519304:ATP1B3 protein, human; D016222:Fibroblast Growth Factor 2; C499076:ATP1A1 protein, human; D000254:Sodium-Potassium-Exchanging ATPase
keywords: ATP1A1; Fibroblast Growth Factor (FGF); Heparan Sulfate; Membrane Recruitment; Membrane Translocation; Na+/K+-ATPase; Phosphoinositide; Plasma Membrane; Tec Kinase; Unconventional Secretion