Identification of a Novel Domain of Fibroblast Growth Factor 2 Controlling Its Angiogenic Properties

Facchiano, Antonio; Russo, Katia; Facchiano, Angelo; Marchis, Francesco De; Facchiano, Francesco; Ribatti, Doménico; Aguzzi, Maria Simona; Capogrossi, Maurizio C.

doi:10.1074/jbc.m209936200

Cited by 41 publications

(22 citation statements)

References 60 publications

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“…Indeed, FGF-2 mutants that fail to interact with RSK2 fail to maintain a sustained RSK2 activity. In line with this observation, the RSK2-interacting FGF-2 residues are not involved in binding to heparin and high affinity receptors, and the corresponding FGF-2 mu- tants enter the nucleus as well as the FGF-2 wild type (13,30,31). Indeed, only the residues Lys-119 and Arg-129 in the FGF-2 nuclear localization signal are critical in regulating nuclear localization of the growth factor (29,32).…”

Section: Discussionsupporting

confidence: 52%

Exogenously Added Fibroblast Growth Factor 2 (FGF-2) to NIH3T3 CellsInteracts with Nuclear Ribosomal S6 Kinase 2 (RSK2) in a Cell Cycle-dependentManner

Soulet

Bailly

Roga

et al. 2005

Journal of Biological Chemistry

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Fibroblast growth factor 2 (FGF-2) has been detected in the nuclei of many tissues and cell lines. Here we demonstrate that FGF-2 added exogenously to NIH3T3 cells enters the nucleus and interacts with the nuclear active 90-kDa ribosomal S6 kinase 2 (RSK2) in a cell cycle-dependent manner. By using purified proteins, FGF-2 is shown to directly interact through two separate domains with two RSK2 domains on both sides of the hydrophobic motif, namely the NH 2 -terminal kinase domain (residues 360 -381) by amino acid Ser-117 and the COOH-terminal kinase domain (residues 388 -400) by amino acids Leu-127 and Lys-128. Moreover, this interaction leads to maintenance of the sustained activation of RSK2 in G 1 phase of the cell cycle. FGF-2 mutants (FGF-2 S117A, FGF-2 L127A, and FGF-2 K128A) that fail to interact in vitro with RSK2 fail to maintain a sustained RSK2 activity in vivo. Fibroblast growth factor 2 (FGF-2)1 is a member of the large FGF family consisting of 30 members in humans (1). It is involved in various cellular processes such as stimulation of DNA synthesis and cell proliferation, as well as differentiation and cell migration. In vitro, numerous cell types synthesize FGF-2 in five molecular isoforms. Four of these isoforms have high molecular masses (21.5,22,24, and 34 kDa) and are initiated at alternative CUG codons. The main form (18 kDa) is initiated at a regular AUG codon. The high molecular mass forms localize exclusively in the nucleus, their NH 2 -terminal extension containing a nuclear localization sequence (2, 3). The 18-kDa isoform is primarily cytoplasmic and, despite the lack of a classical signal peptide, is released by a mechanism bypassing the classical export route taken by most secreted proteins via the endoplasmic reticulum and the Golgi apparatus (4).The pleiotropic effects exhibited by 18-kDa FGF-2 reflect an intricate combinatorial process involving interactions between the growth factor, any of four closely related high affinity transmembrane tyrosine kinase receptors (FGFR1-4), and low affinity binding sites corresponding to the naturally heterogeneous glycosaminoglycan chains of heparan sulfate proteoglycans. The interaction of FGF-2 with its receptor induces a phosphorylation cascade that results in the activation of signalization pathways. Furthermore, in addition to interactions with cell surface receptors, several growth factors enter the nucleus of target cells, either alone or associated with their receptors (5-9). Nuclear translocation of internalized FGF-1 and FGF-2 is an essential step in their mitogenic activity (10 -12). FGF-2 signaling through both FGF receptors and nuclear targets is required for the stimulation of cell proliferation (13,14). These data show that nuclear localization is a general phenomenon for some growth factors, suggesting nuclear functions independent of the functions as extracellular factors.For the understanding of the nuclear functions of FGF-2, identification of interacting proteins is a crucial step. Here, we report that the exogenously added...

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Section: Discussionsupporting

confidence: 52%

Exogenously Added Fibroblast Growth Factor 2 (FGF-2) to NIH3T3 CellsInteracts with Nuclear Ribosomal S6 Kinase 2 (RSK2) in a Cell Cycle-dependentManner

Soulet

Bailly

Roga

et al. 2005

Journal of Biological Chemistry

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“…In parallel, FGF2 induces a proangiogenic response by acting on FGFR1-expressing endothelial cells via a paracrine mechanism of action (8), thus supporting tumor growth and hematogenous dissemination of metastatic cells. In keeping with the role of the FGF2/FGFR1 system in melanoma, antisense targeting of FGF2/FGFR1 (14), FGF2-derived decoy peptides (35,36), and anti-FGF2 monoclonal antibodies (25) suppress murine melanoma growth and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Long Pentraxin-3 Inhibits Epithelial–Mesenchymal Transition in Melanoma Cells

Ronca

Salle

Giacomini

et al. 2013

Molecular Cancer Therapeutics

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During melanoma progression, malignant melanocytes are reprogrammed into mesenchymal-like cells through to an epithelial-mesenchymal transition (EMT) process associated with the acquisition of an invasive, prometastatic phenotype. The fibroblast growth factor-2 (FGF2)/FGF receptor (FGFR) system plays a pivotal role in melanoma, leading to autocrine/paracrine induction of tumor cell proliferation and angiogenesis. Long pentraxin-3 (PTX3) interacts with FGF2, and other FGF family members, inhibiting FGF-dependent neovascularization and tumor growth. Here, PTX3 protein and the PTX3-derived acetylated pentapeptide Ac-ARPCA-NH 2 inhibit FGF2-driven proliferation and downstream FGFR signaling in murine melanoma B16-F10 cells. Moreover, human PTX3-overexpressing hPTX_B16-F10 cells are characterized by the reversed transition from a mesenchymal to an epithelial-like appearance, inhibition of cell proliferation, loss of clonogenic potential, reduced motility and invasive capacity, downregulation of various mesenchymal markers, and upregulation of the epithelial marker E-cadherin. Accordingly, PTX3 affects cell proliferation and EMT transition in human A375 and A2058 melanoma cells. Also, hPTX_B16-F10 cells showed a reduced tumorigenic and metastatic activity in syngeneic C57BL/6 mice. In conclusion, PTX3 inhibits FGF/FGFR-driven EMT in melanoma cells, hampering their tumorigenic and metastatic potential. These data represent the first experimental evidence about a nonredundant role of the FGF/FGFR system in the modulation of the EMT process in melanoma and indicate that PTX3 or its derivatives may represent the basis for the design of novel therapeutic approaches in FGF/FGFRdependent tumors, including melanoma. Mol Cancer Ther; 12(12); 2760-71. Ó2013 AACR.

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“…20,21 Briefly, FGF-2 (0.5 M) in PBS was incubated with 4.5 mM EZ-Linksulfo-NHSbiotin (Pierce) for 30 minutes at room temperature (RT). The excess reagent was quenched by 154 mM Tris-HCl (pH 7.4) for 30 minutes at RT.…”

Section: Fgf-2 Internalizationmentioning

confidence: 99%

Heterodimerization of FGF-receptor 1 and PDGF-receptor-α: a novel mechanism underlying the inhibitory effect of PDGF-BB on FGF-2 in human cells

Faraone

Aguzzi

Ragone

et al. 2006

Blood

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Previous evidence has shown that platelet-derived growth factor-BB (PDGF-BB) and fibroblast growth factor-2 (FGF-2) directly interact with high affinity, leading to potent reciprocal inhibitory effects on bovine endothelial cells and rat vascular smooth muscle cells. In this study, we report that PDGF-BB inhibits a series of FGF-2-induced events, such as proliferation of human umbilical vein endothelial cells (

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Identification of a Novel Domain of Fibroblast Growth Factor 2 Controlling Its Angiogenic Properties

Cited by 41 publications

References 60 publications

Exogenously Added Fibroblast Growth Factor 2 (FGF-2) to NIH3T3 CellsInteracts with Nuclear Ribosomal S6 Kinase 2 (RSK2) in a Cell Cycle-dependentManner

Exogenously Added Fibroblast Growth Factor 2 (FGF-2) to NIH3T3 CellsInteracts with Nuclear Ribosomal S6 Kinase 2 (RSK2) in a Cell Cycle-dependentManner

Long Pentraxin-3 Inhibits Epithelial–Mesenchymal Transition in Melanoma Cells

Heterodimerization of FGF-receptor 1 and PDGF-receptor-α: a novel mechanism underlying the inhibitory effect of PDGF-BB on FGF-2 in human cells

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