Synergism between Hedgehog-GLI and EGFR Signaling in Hedgehog-Responsive Human Medulloblastoma Cells Induces Downregulation of Canonical Hedgehog-Target Genes and Stabilized Expression of GLI1
Figure 8
. Molecular interactions between Hedgehog and EGF signaling pathways occur on the transcriptional level. Rectangular symbols indicate proteins, oval symbols reflect transcripts. Protein translocation is shown as dashed grey lines, ligand-induced activation of signaling pathways mediated by phosphorylation events is shown as dashed red lines and induction of protein expression as blue lines. Proteins and/or transcripts are produced in response to EGF and/or Shh-N signaling. Release of IL8 is shown as an example of crosstalk induced enhanced secretion of tumor-promoting inflammatory extracellular proteins. GLI1-A and AP-1 interact on the transcriptional level to enhance production of canonical EGF target genes. Numerous phosphoproteins are activated by EGFR-signaling with PI3K/AKT and MEK/ERK signaling as major downstream signaling events. However, both pathways do neither contribute to a stabilization of GLI1 on the protein level nor do they contribute to the observed silencing of canonical Hedgehog target genes on the transcript level. Low activity EGFR signaling events such might play a role in this process or might be mediated by EGFR-induced miRs.