Context-dependent signal integration by the GLI code: the oncogenic load, pathways, modifiers and implications for cancer therapy.
Bottom Line: Here, the acquisition of GLI(A) levels above a given threshold is predicted to lead to advanced malignant stages.In this review we highlight the concepts of the GLI code, the oncogenic load, the context-dependency of GLI action, and different modes of signaling integration such as that of HH and EGF.Targeting the GLI code directly or indirectly promises therapeutic benefits beyond the direct blockade of individual pathways.
Affiliation: Department of Molecular Biology, University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria. Electronic address: email@example.com.Show MeSH
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Mentions: In this context, cooperation of EGFR with GLI1 and GLI2 depends on activation of MEK/ERK signaling while PI3K/AKT function is dispensable downstream of EGFR. MEK/ERK induced phosphorylation and activation of the JUN/AP1 transcription factor is the critical event at the terminal end of the EGFR cascade, inducing binding of activated JUN and GLI to common HH-EGFR target promoters, thereby cooperatively regulating target gene expression and transformation [92,93]. It is noteworthy that although basically all receptor tyrosine (RTK) pathways (e.g., HGF, VEGF or FGF) activate MEK/ERK, this is context-dependent as not all of them synergize with HH-GLI in human keratinocytes, possibly because they fail to activate JUN/AP1 in these cells . So far, only EGFR and PDGFRA  signaling have been identified as being able to stimulate both MEK/ERK and JUN/AP1 and synergize with HH-GLI in basal cell carcinoma (BCC) (Fig. 4). Importantly, the beneficial effect of EGFR blockade in HH-driven BCC and pancreatic cancer models can be synergistically improved by combined targeting of both pathways [90,93,108].
Affiliation: Department of Molecular Biology, University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria. Electronic address: firstname.lastname@example.org.