Role of epithelial cell fibroblast growth factor receptor substrate 2α in prostate development, regeneration and tumorigenesis

Abstract

The fibroblast growth factor (FGF) regulates a broad spectrum of biological activities by activation of transmembrane FGF receptor (FGFR) tyrosine kinases and their coupled intracellular signaling pathways. FGF receptor substrate 2alpha (FRS2alpha) is an FGFR interactive adaptor protein that links multiple signaling pathways to the activated FGFR kinase. We previously showed that FGFR2 in the prostate epithelium is important for branching morphogenesis and for the acquisition of the androgen responsiveness. Here we show in mice that FRS2alpha is uniformly expressed in the epithelial cells of developing prostates, whereas it is expressed only in basal cells of the mature prostate epithelium. However, expression of FRS2alpha was apparent in luminal epithelial cells of regenerating prostates and prostate tumors. To investigate FRS2alpha function in the prostate, the Frs2alpha alleles were ablated specifically in the prostatic epithelial precursor cells during prostate development. Similar to the ablation of Fgfr2, ablation of Frs2alpha disrupted MAP kinase activation, impaired prostatic ductal branching morphogenesis and compromised cell proliferation. Unlike the Fgfr2 ablation, disrupting Frs2alpha had no effect on the response of the prostate to androgens. More importantly, ablation of Frs2alpha inhibited prostatic tumorigenesis induced by oncogenic viral proteins. The results suggest that FRS2alpha-mediated signals in prostate epithelial cells promote branching morphogenesis and proliferation, and that aberrant activation of FRS2-linked pathways might promote tumorigenesis. Thus, the prostate-specific Frs2alpha(cn) mice provide a useful animal model for scrutinizing the molecular mechanisms underlying prostatic development and tumorigenesis.

Use of protein array to investigate receptor tyrosine kinases activated in gastric cancer

“…EphA4 was activated in all gastric cancer tissues and other cell lines except MKN1 used in the present study. Overexpression of EGFR, ErbB2, FGFR1, FGFR2·, EphA4 has been already reported in gastric cancer (26,(28)(29)(30)(31). The previous report support our results on the various RTKs activated in gastric cancer derived from the protein array used in this study.…”

The use of protein array to identify targetable receptor tyrosine kinases for treatment of human colon cancer

“…In addition, c-Ret and EphA4 were also activated in human colon cancer tissue. Overexpression of ErbB2, FGFR1, FGFR2a, c-Ret and EphA4 have already been reported in various cancers including colon cancer (14,(35)(36)(37)(38)(39). These reports support our result on the various RTKs detected from the protein array used in this study.…”

Molecular genetics of prostate cancer: new prospects for old challenges

“…For example, ligands and inhibitors for the canonical Wnt/b-catenin as well as noncanonical pathways are expressed in both epithelial and mesenchymal compartments during early prostate organogenesis (Pritchard and Nelson 2008), and abrogation of noncanonical Wnt5a signaling leads to defects in ductal morphogenesis (Huang et al 2009). In addition, the FGF pathway is clearly required for prostate formation, as null mutants for the mesenchymally expressed Fgf10 mostly lack prostate budding , while conditional deletion of Fgfr2, which encodes the receptor for FGF10, or the downstream signaling component Frs2a in prostate epithelium results in defects in branching morphogenesis Zhang et al 2008). Finally, the Hedgehog signaling pathway is also involved in prostate formation, as the Shh ligand is expressed in urogenital epithelium; the downstream components Smo, Ptc1, and Gli1 are expressed in urogenital mesenchyme (Lamm et al 2002;Freestone et al 2003;Berman et al 2004); and loss of Shh pathway activity results in loss of prostate formation and/or defective ductal branching (Podlasek et al 1999;Freestone et al 2003;Berman et al 2004).…”

“…The Pb-Cre4 driver has been used by many laboratories for the conditional deletion of Pten as well as other genes of interest Bruxvoort et al 2007). Another popular Cre driver is the Nkx3.1-Cre knock-in allele, which expresses Cre recombinase specifically in the prostate epithelium, but also in several other tissues during embryogenesis (Stanfel et al 2006;Lin et al 2007;Thomsen et al 2008;Zhang et al 2008).…”