Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2015 Aug 07;29032:19653-65. doi: 10.1074/jbc.M115.644633.
Show Gene links
Show Anatomy links
RasGAP Shields Akt from Deactivating Phosphatases in Fibroblast Growth Factor Signaling but Loses This Ability Once Cleaved by Caspase-3.
Cailliau K, Lescuyer A, Burnol AF, Cuesta-Marbán Á, Widmann C, Browaeys-Poly E.
???displayArticle.abstract??? Fibroblast growth factor receptors (FGFRs) are involved in proliferative and differentiation physiological responses. Deregulation of FGFR-mediated signaling involving the Ras/PI3K/Akt and the Ras/Raf/ERKMAPK pathways is causally involved in the development of several cancers. The caspase-3/p120 RasGAP module is a stress sensor switch. Under mild stress conditions, RasGAP is cleaved by caspase-3 at position 455. The resulting N-terminal fragment, called fragment N, stimulates anti-death signaling. When caspase-3 activity further increases, fragment N is cleaved at position 157. This generates a fragment, called N2, that no longer protects cells. Here, we investigated in Xenopus oocytes the impact of RasGAP and its fragments on FGF1-mediated signaling during G2/M cell cycle transition. RasGAP used its N-terminal Src homology 2 domain to bind FGFR once stimulated by FGF1, and this was necessary for the recruitment of Akt to the FGFR complex. Fragment N, which did not associate with the FGFR complex, favored FGF1-induced ERK stimulation, leading to accelerated G2/M transition. In contrast, fragment N2 bound the FGFR, and this inhibited mTORC2-dependent Akt Ser-473 phosphorylation and ERK2 phosphorylation but not phosphorylation of Akt on Thr-308. This also blocked cell cycle progression. Inhibition of Akt Ser-473 phosphorylation and entry into G2/M was relieved by PHLPP phosphatase inhibition. Hence, full-length RasGAP favors Akt activity by shielding it from deactivating phosphatases. This shielding was abrogated by fragment N2. These results highlight the role played by RasGAP in FGFR signaling and how graded stress intensities, by generating different RasGAP fragments, can positively or negatively impact this signaling.
Alessi,
Mechanism of activation of protein kinase B by insulin and IGF-1.
1996, Pubmed
Alessi,
Mechanism of activation of protein kinase B by insulin and IGF-1.
1996,
Pubmed Anandappa,
Comparative expression of fibroblast growth factor mRNAs in benign and malignant breast disease.
1994,
Pubmed Annibaldi,
Revisiting G3BP1 as a RasGAP binding protein: sensitization of tumor cells to chemotherapy by the RasGAP 317-326 sequence does not involve G3BP1.
2011,
Pubmed Annibaldi,
TAT-RasGAP317-326-mediated tumor cell death sensitization can occur independently of Bax and Bak.
2014,
Pubmed Annibaldi,
Role of the sub-cellular localization of RasGAP fragment N2 for its ability to sensitize cancer cells to genotoxin-induced apoptosis.
2009,
Pubmed Barras,
Inhibition of cell migration and invasion mediated by the TAT-RasGAP317-326 peptide requires the DLC1 tumor suppressor.
2014,
Pubmed Barras,
Fragment N2, a caspase-3-generated RasGAP fragment, inhibits breast cancer metastatic progression.
2014,
Pubmed Brognard,
PHLiPPing the switch on Akt and protein kinase C signaling.
2008,
Pubmed Browaeys-Poly,
Transduction cascades initiated by fibroblast growth factor 1 on Xenopus oocytes expressing MDA-MB-231 mRNAs. Role of Grb2, phosphatidylinositol 3-kinase, Src tyrosine kinase, and phospholipase Cgamma.
2001,
Pubmed
,
Xenbase Browaeys-Poly,
ERK2 is required for FGF1-induced JNK1 phosphorylation in Xenopus oocyte expressing FGF receptor 1.
2005,
Pubmed
,
Xenbase Browaeys-Poly,
Signal transduction pathways triggered by fibroblast growth factor receptor 1 expressed in Xenopus laevis oocytes after fibroblast growth factor 1 addition. Role of Grb2, phosphatidylinositol 3-kinase, Src tyrosine kinase, and phospholipase Cgamma.
2000,
Pubmed
,
Xenbase Browaeys-Poly,
Akt interaction with PLC(gamma) regulates the G(2)/M transition triggered by FGF receptors from MDA-MB-231 breast cancer cells.
2009,
Pubmed
,
Xenbase Bulat,
RasGAP-derived fragment N increases the resistance of beta cells towards apoptosis in NOD mice and delays the progression from mild to overt diabetes.
2011,
Pubmed Cailliau,
A microinjectable biological system, the Xenopus oocyte, as an approach to understanding signal transduction protein function.
2009,
Pubmed
,
Xenbase Cailliau,
RasGAP is involved in signal transduction triggered by FGF1 in Xenopus oocytes expressing FGFR1.
2001,
Pubmed
,
Xenbase Chirgwin,
Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease.
1979,
Pubmed Crowell,
Targeting the AKT protein kinase for cancer chemoprevention.
2007,
Pubmed Cybulski,
TOR complex 2: a signaling pathway of its own.
2009,
Pubmed Dieci,
Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives.
2013,
Pubmed Dillon,
A crucial role for fibroblast growth factor signaling in embryonic mammary gland development.
2004,
Pubmed Duchesne,
Identification of the SH3 domain of GAP as an essential sequence for Ras-GAP-mediated signaling.
1993,
Pubmed
,
Xenbase Eswarakumar,
Cellular signaling by fibroblast growth factor receptors.
2005,
Pubmed Fernig,
Differential regulation of FGF-1 and -2 mitogenic activity is related to their kinetics of binding to heparan sulfate in MDA-MB-231 human breast cancer cells.
2000,
Pubmed Ferrell,
Xenopus oocyte maturation: new lessons from a good egg.
1999,
Pubmed
,
Xenbase Furdui,
Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction.
2006,
Pubmed Gigoux,
Identification of Aurora kinases as RasGAP Src homology 3 domain-binding proteins.
2002,
Pubmed Gurdon,
Use of frog eggs and oocytes for the study of messenger RNA and its translation in living cells.
1971,
Pubmed
,
Xenbase Hemmings,
PI3K-PKB/Akt pathway.
2012,
Pubmed Hu,
Tandem SH2 binding sites mediate the RasGAP-RhoGAP interaction: a conformational mechanism for SH3 domain regulation.
1997,
Pubmed Itoh,
Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease.
2011,
Pubmed Jacquemier,
Expression of the FGFR1 gene in human breast-carcinoma cells.
1994,
Pubmed Khalil,
Caspase-3 protects stressed organs against cell death.
2012,
Pubmed Khalil,
Caspase-3 and RasGAP: a stress-sensing survival/demise switch.
2014,
Pubmed Kumar,
AKT kinase pathway: a leading target in cancer research.
2013,
Pubmed Kuo,
Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.
2008,
Pubmed Lemmon,
Pleckstrin homology (PH) domains and phosphoinositides.
2007,
Pubmed Liu,
Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus.
2014,
Pubmed Luqmani,
Expression of basic fibroblast growth factor, FGFR1 and FGFR2 in normal and malignant human breast, and comparison with other normal tissues.
1992,
Pubmed Manning,
AKT/PKB signaling: navigating downstream.
2007,
Pubmed Martin,
Multidrug-resistant breast cancer: current perspectives.
2014,
Pubmed Mendoza,
PHLPPing it off: phosphatases get in the Akt.
2007,
Pubmed Michod,
TAT-RasGAP317-326 requires p53 and PUMA to sensitize tumor cells to genotoxins.
2007,
Pubmed Michod,
Effect of RasGAP N2 fragment-derived peptide on tumor growth in mice.
2009,
Pubmed Michod,
A RasGAP-derived cell permeable peptide potently enhances genotoxin-induced cytotoxicity in tumor cells.
2004,
Pubmed Moore,
mTORC2 protein complex-mediated Akt (Protein Kinase B) Serine 473 Phosphorylation is not required for Akt1 activity in human platelets [corrected].
2011,
Pubmed Nebreda,
Regulation of the meiotic cell cycle in oocytes.
2000,
Pubmed
,
Xenbase Ornitz,
Fibroblast growth factors.
2001,
Pubmed Pamonsinlapatham,
p120-Ras GTPase activating protein (RasGAP): a multi-interacting protein in downstream signaling.
2009,
Pubmed Pascreau,
Aurora-A kinase Ser349 phosphorylation is required during Xenopus laevis oocyte maturation.
2008,
Pubmed
,
Xenbase Penault-Llorca,
Expression of FGF and FGF receptor genes in human breast cancer.
1995,
Pubmed Pittet,
Effect of the TAT-RasGAP(317-326) peptide on apoptosis of human malignant mesothelioma cells and fibroblasts exposed to meso-tetra-hydroxyphenyl-chlorin and light.
2007,
Pubmed Pomerance,
The Ras-GTPase-activating protein SH3 domain is required for Cdc2 activation and mos induction by oncogenic Ras in Xenopus oocytes independently of mitogen-activated protein kinase activation.
1996,
Pubmed
,
Xenbase Renaud,
Expression and regulation by serum of multiple FGF1 mRNA in normal transformed, and malignant human mammary epithelial cells.
1996,
Pubmed Rong,
Molecular modeling studies of the Akt PH domain and its interaction with phosphoinositides.
2001,
Pubmed Ryan,
Identification of phosphorylated proteins associated with the fibroblast growth factor receptor type I during early Xenopus development.
1998,
Pubmed
,
Xenbase Sarkissian,
Progesterone and insulin stimulation of CPEB-dependent polyadenylation is regulated by Aurora A and glycogen synthase kinase-3.
2004,
Pubmed
,
Xenbase Stebbins-Boaz,
CPEB controls the cytoplasmic polyadenylation of cyclin, Cdk2 and c-mos mRNAs and is necessary for oocyte maturation in Xenopus.
1996,
Pubmed
,
Xenbase Steelman,
Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging.
2011,
Pubmed Vincent,
Akt phosphorylation on Thr308 but not on Ser473 correlates with Akt protein kinase activity in human non-small cell lung cancer.
2011,
Pubmed Wesche,
Fibroblast growth factors and their receptors in cancer.
2011,
Pubmed Woodcock,
p120 Ras GTPase-activating protein associates with fibroblast growth factor receptors in Drosophila.
2004,
Pubmed Yang,
Solution structure of GAP SH3 domain by 1H NMR and spatial arrangement of essential Ras signaling-involved sequence.
1994,
Pubmed Yang,
Surviving the kiss of death.
2004,
Pubmed Yang,
Partial cleavage of RasGAP by caspases is required for cell survival in mild stress conditions.
2004,
Pubmed Yang,
Antiapoptotic signaling generated by caspase-induced cleavage of RasGAP.
2001,
Pubmed Yang,
Impaired Akt activity down-modulation, caspase-3 activation, and apoptosis in cells expressing a caspase-resistant mutant of RasGAP at position 157.
2005,
Pubmed Yang,
The RasGAP N-terminal fragment generated by caspase cleavage protects cells in a Ras/PI3K/Akt-dependent manner that does not rely on NFkappa B activation.
2002,
Pubmed Yoshimura,
The expression and localization of fibroblast growth factor-1 (FGF-1) and FGF receptor-1 (FGFR-1) in human breast cancer.
1998,
Pubmed Yue,
Ras GTPase-activating protein binds to Akt and is required for its activation.
2004,
Pubmed
