Control of CREB-binding protein signaling by nuclear fibroblast growth factor receptor-1: a novel mechanism of gene regulation.
In integrative nuclear fibroblast growth factor receptor-1 (FGFR1) signaling a newly synthesized FGFR1 translocates to the nucleus to stimulate cell differentiation and associated gene activities. The present study shows that FGFR1 accumulates and interacts with the transcriptional co-activator CREB-binding protein (CBP) in nuclear speckle domains in the developing brain and in neural progenitor-like cells in vitro, which accompanies differentiation and postmitotic growth. Cell differentiation and gene activation by nuclear FGFR1 do not require tyrosine kinase activity. Instead, FGFR1 stimulates transcription in cooperation with CBP by increasing recruitment of RNA polymerase II and histone acetylation at the active gene promoter. FGFR1 is a multifactorial protein whose N terminus interacts with CBP and C terminus with ribosomal S6 kinase 1 (RSK1). Nuclear FGFR1 augments CBP-mediated transcription by 1) releasing the CBP C-terminal domain from RSK1 inhibition and 2) activating the CBP N-terminal domain. The interaction of FGFR1 with CBP and RSK1 allows activation of gene transcription and may play a role in cell differentiation.
Fang
Xiaohong
X
Department of Pathology and Anatomical Sciences, State University of New York, Buffalo, New York 14214, USA.
Stachowiak
Ewa K
EK
Dunham-Ems
Star M
SM
Klejbor
Ilona
I
Stachowiak
Michal K
MK
D019943:Amino Acid Substitution; D050882:CREB-Binding Protein; D002454:Cell Differentiation / Q000502:physiology; D002467:Cell Nucleus / Q000502:physiology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D009687:Nuclear Proteins; D017468:Receptors, Fibroblast Growth Factor; D015534:Trans-Activators; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D012319:RNA Polymerase II