title: Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer.
abstract: In the absence of extracellular stimulation the adaptor protein growth factor receptor-bound protein (Grb2) and the phospholipase Plcγ1 compete for the same binding site on fibroblast growth factor receptor 2 (FGFR2). Reducing cellular Grb2 results in upregulation of Plcγ1 and depletion of the phospholipid PI(4,5)P2. The functional consequences of this event on signaling pathways are unknown. We show that the decrease in PI(4,5)P2 level under non-stimulated conditions inhibits PTEN activity leading to the aberrant activation of the oncoprotein Akt. This results in excessive cell proliferation and tumor progression in a xenograft mouse model. As well as defining a novel mechanism of Akt phosphorylation with important therapeutic consequences, we also demonstrate that differential expression levels of FGFR2, Plcγ1 and Grb2 correlate with patient survival. Oncogenesis through fluctuation in the expression levels of these proteins negates extracellular stimulation or mutation and defines them as novel prognostic markers in ovarian cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Unit 1000, Houston, TX, USA.|School of Molecular and Cellular Biology, University of Leeds, Leeds, UK.
authors.forename: Z
authors.initials: Z
authors.lastname: Timsah
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Unit 1000, Houston, TX, USA.|Center for Biomolecular Structure and Function, The University of Texas MD Anderson Cancer Center, Unit 1000, Houston, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Ahmed
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: C
authors.identifier: 0000-0002-4848-0168
authors.initials: C
authors.lastname: Ivan
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds, Leeds, UK.|Department of Molecular and Cellular Biology, Stem Cells and Regenerative Medicine Center, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Berrout
authors.affiliation: Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Unit 63, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Gagea
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Medical School, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G N A
authors.initials: GN
authors.lastname: Pena
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Unit 63, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Vallien
authors.affiliation: Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Unit 1472, Houston, TX, USA.
authors.forename: C V
authors.initials: CV
authors.lastname: Kingsley
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Medical School, Houston, TX, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Hancock
authors.affiliation: Department of Pathology/Laboratory Medicine, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Unit 1010, Houston, TX, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Gladden
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M-C
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Medical School, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bogdanov
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Unit 1000, Houston, TX, USA.|School of Molecular and Cellular Biology, University of Leeds, Leeds, UK.|Center for Biomolecular Structure and Function, The University of Texas MD Anderson Cancer Center, Unit 1000, Houston, TX, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Ladbury
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D051380:GRB2 Adaptor Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D051058:Oncogene Protein v-akt / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010716:Phosphatidylinositols / Q000378:metabolism; D051966:Phospholipase C gamma / Q000096:biosynthesis / Q000235:genetics*; D011379:Prognosis; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D010716:Phosphatidylinositols; D019869:Phosphatidylinositol 3-Kinases; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C522157:PLCG1 protein, human; D051966:Phospholipase C gamma