FGF signaling inhibitor, SPRY4, is evolutionarily conserved target of WNT signaling pathway in progenitor cells

Abstract

Abstract. WNT, FGF and Hedgehog signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. FGF16, FGF18, and FGF20 genes are targets of WNT-mediated TCF/LEF-ß-catenin-BCL9/BCL9L-PYGO transcriptional complex. SPROUTY (SPRY) and SPRED family genes encode inhibitors for receptor tyrosine kinase signaling cascades, such as those of FGF receptor family members and EGF receptor family members. Here, transcriptional regulation of SPRY1, SPRY2, SPRY3, SPRY4, SPRED1, SPRED2, and SPRED3 genes by WNT/ß-catenin signaling cascade was investigated by using bioinformatics and human intelligence (humint). Because double TCF/LEFbinding sites were identified within the 5'-promoter region of human SPRY4 gene, comparative genomics analyses on SPRY4 orthologs were further performed. SPRY4-FGF1 locus at human chromosome 5q31.3 and FGF2-NUDT6-SPATA5-SPRY1 locus at human chromosome 4q27-q28.1 were paralogous regions within the human genome. Chimpanzee SPRY4 gene was identified within NW_107083.1 genome sequence. Human, chimpanzee, rat and mouse SPRY4 orthologs, consisting of three exons, were well conserved. SPRY4 gene was identified as the evolutionarily conserved target of WNT/ ß-catenin signaling pathway based on the conservation of double TCF/LEF-binding sites within 5'-promoter region of mammalian SPRY4 orthologs. Human SPRY4 mRNA was expressed in embryonic stem (ES) cells, brain, pancreatic islet, colon cancer, head and neck tumor, melanoma, and pancreatic cancer. WNT signaling activation in progenitor cells leads to the growth regulation of progenitor cells themselves through SPRY4 induction, and also to the growth stimulation of proliferating cells through FGF secretion. Epigenetic silencing and loss-of-function mutations of SPRY4 gene in progenitor cells could lead to carcinogenesis. SPRY4 is the pharmacogenomics target in the fields of oncology and regenerative medicine. IntroductionWNT, FGF, and Hedgehog signaling pathways network together in a variety of cellular processes, such as stem cell differentiation cascade, body axis formation, angiogenesis, organogenesis during embryogenesis, adult tissue regeneration during chronic persistent inflammation, cell fate determination and cancer cell proliferation during carcinogenesis (1-11).Canonical WNT signals are transduced through Frizzled receptors and LRP5/6 co-receptors to activate transcription of target genes, such as FGF18, FGF20, CCND1 and MYC, based on the transcriptional complex consisting of TCF/LEF, ß-catenin, BCL9/BCL9L, and PYGO1/PYGO2 (12-21). FGF signals are transduced through FGF receptors and FRS2 docking protein to activate RAS-RAF-MAPKK-MAPK signaling cascade as well as PI3K-AKT signaling cascade (4,5,(22)(23)(24). Hedgehog signals are transduced through Patched receptors and Smoothened signal transducers to activate transcription of target genes, such as PTCH1, SFRP1, CCND2 and FOXM1 genes, based on active form of GLI family transcription factors (6-9,25-28). WNT, FGF, and Hedgehog signaling pathways network together d...

A bi-modal function of Wnt signalling directs an FGF activity gradient to spatially regulate neuronal differentiation in the midbrain

“…Sprouty genes have been considered to be principally FGF target genes and interpretation of Sprouty function in vivo has relied on this assumption (Jászai et al, 2003;Trokovic et al, 2003;Paridaen et al, 2009). However, human SPRY4 has conserved LEF binding sites in its promoter (Katoh and Katoh, 2006) and Spry4 is upregulated by Wnt7a (Tennis et al, 2010), suggesting that Sprouty genes might also be Wnt regulated. Our results show that spry4 does not respond similarly to pea3 and her5 when FGF or Wnt signalling are manipulated and, unlike these FGF-responsive genes, spry4 responds rapidly to changes in Wnt signalling.…”

Notch signaling in gastrointestinal tract (Review)

“…Notch, WNT, FGF, Hedgehog and BMP signaling pathways constitute the stem cell signaling network regulating the balance of self-renewal, proliferation and differentiation among stem and progenitor (transitamplifying) cell population (33)(34)(35)(36)(37)(38)(39)(40)(41)(42). Notch signaling plays a key role in the stem cell signaling network through the interaction with other signaling pathways.…”

Hedgehog signaling pathway and gastrointestinal stem cell signaling network (Review)

“…WNT signaling plays a key role for the maintenance of intestinal epithelium (37)(38)(39)(40)(41)(42). WNT signaling is activated in the progenitor (transit-amplifying) region around the bottom of intestinal crypt, while Hedgehog signaling in the differentiated region around the surface of intestinal villi (33).…”