![]() Based on compelling evidence from both cell-based FGF2 secretion experiments and biochemical in vitro studies, unconventional secretion of FGF2 was shown to follow a type I mechanism that is based on direct protein translocation across the plasma membrane ( La Venuta et al., 2015 Zhang and Schekman, 2013 Malhotra, 2013 Nickel, 2005 Schäfer et al., 2004). Two of these pathways concern soluble proteins derived from the cytoplasm that are transported into the extracellular space by either direct protein translocation across the plasma membrane (type I unconventional secretion) or vesicular mechanisms involving endosomal compartments (type III unconventional secretion) ( Rabouille et al., 2012 Zhang and Schekman, 2013 Piccioli and Rubartelli, 2013). The term unconventional secretion has been used for four different pathways of protein transport towards the plasma membrane and the extracellular space ( Rabouille et al., 2012). This process is believed to represent a frequent cause of tumor cell resistance against conventional anti-cancer therapies.Īs opposed to other FGF family members, FGF2 lacks a signal peptide and is transported into the extracellular space by an ER/Golgi-independent mechanism ( La Venuta et al., 2015 Nickel, 2011 Nickel and Rabouille, 2009, 2008). In addition, FGF2 acts as a survival factor that inhibits tumor cell apoptosis by an autocrine secretion-signaling loop ( Noh et al., 2014 Pardo et al., 2006). This is particularly evident in the context of cancer with FGF2 being a major mediator of tumor-induced angiogenesis ( Presta et al., 2005). FGF2 is the prototype member of this family that, beyond the functions of FGFs in normal cell growth and differentiation, plays critical roles under pathophysiological conditions ( Akl et al., 2016). They are of critical importance for physiological processes such as embryonic development, tissue regeneration, wound repair and hematopoiesis ( Bikfalvi et al., 1997). Our combined findings establish a novel type of self-sustained protein translocation across membranes revealing the molecular basis of the unconventional secretory pathway of FGF2.įibroblast Growth Factors (FGFs) form a family of more than 20 potent mitogens that stimulate the growth of a wide range of cells including fibroblasts and endothelial cells ( Bikfalvi et al., 1997). ![]() Based on atomistic molecular dynamics simulations, we propose a mechanism that drives PI(4,5)P 2 dependent oligomerization of FGF2. Vectorial translocation of FGF2 across the membrane is governed by sequential and mutually exclusive interactions with PI(4,5)P 2 and heparan sulfates on opposing sides of the membrane. The latter serve as dynamic translocation intermediates of FGF2 with a subunit number in the range of 8-12 FGF2 molecules. FGF2 membrane translocation is thermodynamically driven by PI(4,5)P 2-induced membrane insertion of FGF2 oligomers. Here, we define the minimal molecular machinery required for FGF2 membrane translocation in a fully reconstituted inside-out vesicle system. This process is mediated by direct translocation across the plasma membrane. Cancer Res 1997 57: 4063–4069.FGF2 is secreted from cells by an unconventional secretory pathway. AAC-11, a novel cDNA that inhibits apoptosis after growth factor withdrawal. Tewari M, Yu M, Ross B, Dean C, Giordano A, Rubin R. FIF, a nuclear putatively antiapoptotic factor, interacts specifically with FGF-2. Van den Berghe L, Laurell H, Huez I, Zanibellato C, Prats H, Bugler B. The high molecular weight isoforms of basic fibroblast growth factor (FGF-2): an insight into an intracrine mechanism. Both normal and tumor cells produce basic fibroblast growth factor. Moscatelli D, Presta M, Joseph-Silverstein J, Rifkin DB. Expression of basic fibroblast growth factor (bFGF) and FGF-receptors in human leukemic cells. ![]() Blood 1999 94: 3334–3339.Īllouche M, Bayard F, Clamens S, Fillola G, Sie P, Amalric F. A high pretreatment serum basic fibroblast growth factor concentration is an independent predictor of poor prognosis in non-Hodgkin's lymphoma. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. ![]() Blood 1999 94: 1077–1085.Īguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D et al. Basic fibroblast growth factor is expressed by CD19/CD11c-positive cells in hairy cell leukemia. Gruber G, Schwarzmeier JD, Shehata M, Hilgarth M, Berger R. ![]()
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