title: The Startling Properties of Fibroblast Growth Factor 2: How to Exit Mammalian Cells without a Signal Peptide at Hand.
abstract: For a long time, protein transport into the extracellular space was believed to strictly depend on signal peptide-mediated translocation into the lumen of the endoplasmic reticulum. More recently, this view has been challenged, and the molecular mechanisms of unconventional secretory processes are beginning to emerge. Here, we focus on unconventional secretion of fibroblast growth factor 2 (FGF2), a secretory mechanism that is based upon direct protein translocation across plasma membranes. Through a combination of genome-wide RNAi screening approaches and biochemical reconstitution experiments, the basic machinery of FGF2 secretion was identified and validated. This includes the integral membrane protein ATP1A1, the phosphoinositide phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), and Tec kinase, as well as membrane-proximal heparan sulfate proteoglycans on cell surfaces. Hallmarks of unconventional secretion of FGF2 are: (i) sequential molecular interactions with the inner leaflet along with Tec kinase-dependent tyrosine phosphorylation of FGF2, (ii) PI(4,5)P2-dependent oligomerization and membrane pore formation, and (iii) extracellular trapping of FGF2 mediated by heparan sulfate proteoglycans on cell surfaces. Here, we discuss new developments regarding this process including the mechanism of FGF2 oligomerization during membrane pore formation, the functional role of ATP1A1 in FGF2 secretion, and the possibility that other proteins secreted by unconventional means make use of a similar mechanism to reach the extracellular space. Furthermore, given the prominent role of extracellular FGF2 in tumor-induced angiogenesis, we will discuss possibilities to develop highly specific inhibitors of FGF2 secretion, a novel approach that may yield lead compounds with a high potential to develop into anti-cancer drugs.
authors.affiliation: Heidelberg University Biochemistry Center, 69120 Heidelberg, Germany.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: La Venuta
authors.affiliation: Heidelberg University Biochemistry Center, 69120 Heidelberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Zeitler
authors.affiliation: Heidelberg University Biochemistry Center, 69120 Heidelberg, Germany.
authors.forename: Julia P
authors.initials: JP
authors.lastname: Steringer
authors.affiliation: Heidelberg University Biochemistry Center, 69120 Heidelberg, Germany.
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Müller
authors.affiliation: Heidelberg University Biochemistry Center, 69120 Heidelberg, Germany. Electronic address: walter.nickel@bzh.uni-heidelberg.de.
authors.forename: Walter
authors.initials: W
authors.lastname: Nickel
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D055503:Protein Multimerization; D021382:Protein Sorting Signals; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D034622:RNA Interference; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate; D019269:Phosphatidylinositol 4,5-Diphosphate; D021382:Protein Sorting Signals; D011505:Protein-Tyrosine Kinases; D000254:Sodium-Potassium-Exchanging ATPase; C089848:Tec protein-tyrosine kinase
keywords: Tec kinase; fibroblast growth factor (FGF); heparan sulfate; membrane transport; phosphoinositides; plasma membrane; protein translocation across membranes; tumor cell biology; unconventional protein secretion