Fibroblast Growth Factor Receptor-1 (FGFR1) Nuclear Dynamics Reveal a Novel Mechanism in Transcription Control

Dunham-Ems, Star; Lee, Yu-Wei; Stachowiak, Ewa K.; Pudavar, Haridas E.; Claus, Piet; Prasad, Paras N.; Stachowiak, Michal K.

doi:10.1091/mbc.e08-06-0600

Cited by 62 publications

(115 citation statements)

References 42 publications

(104 reference statements)

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“…In the nuclear pathway, an atypical transmembrane domain in FGFR1 allows newly translated immobile receptor to be released from the pre‐Golgi membrane into cytosol generating a highly mobile protein in a process that involves proteasomes and is facilitated by the FGF‐2 ligand, and ribosomal S6 kinase (Dunham‐Ems et al, 2006, 2009). The nuclear transport of FGFR1 is mediated by importin‐β (Reilly and Maher, 2001).…”

Section: Constitutive Plasma Membrane and Regulated Nuclear Targetingmentioning

confidence: 99%

“…This is the reason that this pathway is referred to as integrative signaling (Stachowiak et al, 2015). FRET and co‐immunoprecipitation assays show that the NLS containing 23 kDa FGF‐2 interacts with nFGFR1 during nuclear transport and in the nucleus while, 18 kDa FGF‐2, which lacks a bipartite NLS, interacts with FGFR1 only in the cytoplasm (Dunham‐Ems et al, 2009). Biophotonic assays, including FLIP and FRAP, have demonstrated that cytoplasmic FGFR1 exists in three separate populations: (1) an immobile, newly synthesized Endoplasmic Reticulum (ER) population; (2) a highly mobile, non‐glycosylated, cytosolic population; and (3) a slowly diffusing, membrane receptor population (Dunham‐Ems et al, 2006).…”

Section: Constitutive Plasma Membrane and Regulated Nuclear Targetingmentioning

confidence: 99%

“…The interaction of CBP with hypo‐glycosylated nFGFR1 was indicated by GST‐CBP pull downs of FGFR1, coimmunoprecipitations of CBP and nFGFR1, and by biophotonics of live cells (Fang et al, 2005; Dunham‐Ems et al, 2009). CBP associates with diverse TFs during their binding to gene regulatory sequences.…”

Section: Nuclear Fgf Receptor‐1 and Creb Binding Protein—an Integratimentioning

confidence: 99%

“…The nFGFR1‐CBP complex activates transcription by recruiting RNA Pol II and acetylating histones (Fang et al, 2005), while RSK1‐bound nFGFR1 phosphorylates TFs and, potentially, other chromatin proteins. (B) Kinetic model of INFS from FRAP mobility measurements (Dunham‐Ems et al, 2009; Stachowiak et al, 2012b). Bimodal analyses of the R1‐EGFP FRAP recovery demonstrate that nuclear FGFR1 contains a hyperkinetic component (“F” Fast recovering t 1/2 < 1 sec; present in nucleoplasm), a hypokinetic component (“S” Slow‐recovering, t 1/2 = 24 sec; chromatin‐associated), and an immobile component (non‐recovering, nuclear matrix‐associated).…”

Section: Nuclear Fgf Receptor‐1 and Creb Binding Protein—an Integratimentioning

confidence: 99%

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Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

Stachowiak

2016

Journal Cellular Physiology

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Genetic experiments have positioned the fgfr1 gene at the top of the gene hierarchy that governs gastrulation, as well as the subsequent development of the major body axes, nervous system, muscles, and bones, by affecting downstream genes that control the cell cycle, pluripotency, and differentiation, as well as microRNAs. Studies show that this regulation is executed by a single protein, the nuclear isoform of FGFR1 (nFGFR1), which integrates signals from development‐initiating factors, such as retinoic acid (RA), and operates at the interface of genomic and epigenomic information. nFGFR1 cooperates with a multitude of transcriptional factors (TFs), and targets thousands of genes encoding for mRNAs, as well as miRNAs in top ontogenic networks. nFGFR1 binds to the promoters of ancient proto‐oncogenes and tumor suppressor genes, in addition to binding to metazoan morphogens that delineate body axes, and construct the nervous system, as well as mesodermal and endodermal tissues. The discovery of pan‐ontogenic gene programming by integrative nuclear FGFR1 signaling (INFS) impacts our understanding of ontogeny, as well as developmental pathologies, and holds new promise for reconstructive medicine, and cancer therapy. J. Cell. Physiol. 231: 1199–1218, 2016. © 2016 The Authors. Journal of Cellular Physiology published by Wiley Periodicals, Inc.

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Section: Constitutive Plasma Membrane and Regulated Nuclear Targetingmentioning

confidence: 99%

Section: Constitutive Plasma Membrane and Regulated Nuclear Targetingmentioning

confidence: 99%

Section: Nuclear Fgf Receptor‐1 and Creb Binding Protein—an Integratimentioning

confidence: 99%

Section: Nuclear Fgf Receptor‐1 and Creb Binding Protein—an Integratimentioning

confidence: 99%

See 2 more Smart Citations

Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

Stachowiak

2016

Journal Cellular Physiology

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“…Moreover, nuclear FGFR1 localizes to nuclear speckles containing snRNPs (49) and the splicing factor SC35 (50). FGF-2 23 -but, surprisingly, not FGF-2 18 -binds to nuclear FGFR1 and regulates its nuclear mobility (51). These data argue for the possibility that FGFR1 could act in RNA metabolism.…”

Section: Discussionmentioning

confidence: 85%

Fibroblast growth factor–2 regulates the stability of nuclear bodies

Bruns

Bergeijk

Lorbeer

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear bodies are distinct subnuclear structures. The survival of motoneuron (SMN) gene is mutated or deleted in patients with the neurodegenerative disease spinal muscular atrophy (SMA). The gene product SMN is a marker protein for one class of nuclear bodies denoted as nuclear gems. SMN has also been found in Cajal bodies, which co-localize with gems in many cell types. Interestingly, SMA patients display a reduced number of gems. Little is known about the regulation of nuclear body formation and stabilization. We have previously shown that a nuclear isoform of the fibroblast growth factor-2 (FGF-2 23 ) binds directly to SMN. In this study, we analyzed the consequences of FGF-2 23 binding to SMN with regard to nuclear body formation. On a molecular level, we showed that FGF-2 23 competed with Gemin2 (a component of the SMN complex that is necessary for gem stabilization) for binding to SMN. Down-regulation of Gemin2 by siRNA caused destabilization of SMN-positive nuclear bodies. This process is reflected in both cellular and in vivo systems by a negative regulatory function of FGF-2 in nuclear body formation: in HEK293 cells, FGF-2 23 decreased the number of SMN-positive nuclear bodies. The same effect could be observed in motoneurons of FGF-2 transgenic mice. This study demonstrates the functional role of a growth factor in the regulation of structural entities of the nucleus. nuclear organization ͉ nuclear structure ͉ spinal muscular atrophy ͉ survival of motoneuron protein

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Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion

et al. 2014

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Pancreatic cancer is characterised by desmoplasia, driven by activated pancreatic stellate cells (PSCs). Over-expression of FGFs and their receptors is a feature of pancreatic cancer and correlates with poor prognosis, but whether their expression impacts on PSCs is unclear. At the invasive front of human pancreatic cancer, FGF2 and FGFR1 localise to the nucleus in activated PSCs but not cancer cells. In vitro, inhibiting FGFR1 and FGF2 in PSCs, using RNAi or chemical inhibition, resulted in significantly reduced cell proliferation, which was not seen in cancer cells. In physiomimetic organotypic co-cultures, FGFR inhibition prevented PSC as well as cancer cell invasion. FGFR inhibition resulted in cytoplasmic localisation of FGFR1 and FGF2, in contrast to vehicle-treated conditions where PSCs with nuclear FGFR1 and FGF2 led cancer cells to invade the underlying extra-cellular matrix. Strikingly, abrogation of nuclear FGFR1 and FGF2 in PSCs abolished cancer cell invasion. These findings suggest a novel therapeutic approach, where preventing nuclear FGF/FGFR mediated proliferation and invasion in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion.

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Fibroblast Growth Factor Receptor-1 (FGFR1) Nuclear Dynamics Reveal a Novel Mechanism in Transcription Control

Cited by 62 publications

References 42 publications

Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

Fibroblast growth factor–2 regulates the stability of nuclear bodies

Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion

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