“Nuclear FGF Receptor‐1 and CREB Binding Protein: An Integrative Signaling Module”

Abstract

In this review we summarize the current understanding of a novel integrative function of Fibroblast Growth Factor Receptor-1 (FGFR1) and its partner CREB Binding Protein (CBP) acting as a nuclear regulatory complex. Nuclear FGFR1 and CBP interact with and regulate numerous genes on various chromosomes. FGFR1 dynamic oscillatory interactions with chromatin and with specific genes, underwrites gene regulation mediated by diverse developmental signals. Integrative Nuclear FGFR1 Signaling (INFS) effects the differentiation of stem cells and neural progenitor cells via the gene-controlling Feed-Forward-And-Gate mechanism. Nuclear accumulation of FGFR1 occurs in numerous cell types and disruption of INFS may play an important role in developmental disorders such as schizophrenia, and in metastatic diseases such as cancer. Enhancement of INFS may be used to coordinate the gene regulation needed to activate cell differentiation for regenerative purposes or to provide interruption of cancer stem cell proliferation.

Membrane and Integrative Nuclear Fibroblastic Growth Factor Receptor (FGFR) Regulation of FGF-23

“…In contrast, HMW-FGF-2 acts in concert with cAMP-dependent pathways to stimulate FGF-23 promoter activity through a FGFR/HMW-FGF-2/CBP/CREB complex that binds to the CRE in the proximal FGF-23 promoter. To our knowledge this is the first report demonstrating a role for the intracrine FGFR1 and CREB nuclear regulator complex regulating FGF-23 hormone transcription in osteoblasts (47).…”

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

“…The nuclear accumulation of the hypoglycosylated nuclear form of FGFR1 (nFGFR1) is stimulated by a variety of developmental signals, including various growth factors (i.e., EGF, NGF, BDNF, BMP), vitamins D and retinoids, hormones, and neurotransmitters, calcium, cyclic AMP, and is inhibited by cell contact receptors. 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).…”

“…Dual plasma membrane and nuclear FGFR1 distribution is observed in developing cells (Stachowiak et al, 2015). For instance in proliferating brain stem cells FGFR1 is cytoplasmic whereas in differentiating neural cells FGFR1 accumulates in the cell nucleus (Stachowiak et al, 2012a).…”

“…Testing function of nFGFR1 by gain and loss experiments—transfection of the constitutively active/nuclear variant FGFR1(SP‐/NLS), in which the cleavable SP is replaced with the NLS of FGF2, provides a means to generate INFS signals directly in the nucleus bypassing the afferent stimuli. Transfection of dominant‐negative variants of FGFR1(SP‐/NLS)(TK‐), which lack the tyrosine kinase (TK) domain, block nFGFR1 function specifically in the cell nucleus (Stachowiak et al, 2012b, 2015). The tyrosine kinase deleted (TK‐) mutant displaces endogenous nFGFR1 from the CBP complex and the gene promoter (Peng et al, 2002).…”

“…Fgfr1 governs gastrulation, as well as development of the major body axes, neural plate, central and peripheral nervous systems, and mesoderm by affecting the genes that control the cell cycle, pluripotency and differentiation (Ciruna et al, 1997; Partanen et al, 1998; Ciruna and Rossant, 2001; Dequeant and Pourquie, 2008) and microRNAs (Bobbs et al, 2012). This regulation is executed by nuclear protein, nFGFR1, which integrates a plethora of development controlling epigenomic signals (Stachowiak et al, 2015). nFGFR1 cooperates with RXR, Nurs and other CBP binding TFs, and targets thousands of genomic loci, including promoters of the mRNA and miRNA genes that reside at the top of the ontogenetic networks (Terranova et al, 2015).…”