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Context-dependent signal integration by the GLI code: the oncogenic load, pathways, modifiers and implications for cancer therapy.

Aberger F, Ruiz I Altaba A - Semin. Cell Dev. Biol. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria. Electronic address: fritz.aberger@sbg.ac.at.

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Modes of HH-EGF signaling integration. (A) Canonical HH-GLI signaling activated by binding of SHH to its receptor PTCH results in ciliary localization of SMOH and subsequent GLI activation (GLIA). HH-GLI signaling alone only activates classical GLI targets including HHIP and GLI1 but fails to induce HH-EGFR cooperation target genes. (B) Concomitant activation of HH-GLI and EGF/PDGF signaling (EGFR or PDGFRA) can lead to synergistic interactions [46,47]. Such interactions can result in (i) cross talk between SHH and EGFR in neural stem cells [105], (ii) enhancement of GLI1 activity by RAS/MEK signaling in melanomas and other tumor cells [65], and/or (iii) synergistic promotion of basal cell carcinoma and pancreatic cancer by selective activation of HH-EGFR target genes such as CXCR4, FGF19, SOX9 and TGFA [90,92,93]. In the latter case, integration of HH-EGFR signaling occurs at the level of common target gene promoters. Activation of EGF signaling induces the RAS/RAF/MEK/ERK cascade eventually leading to activation of GLI1 or/and of the JUN/AP1 transcription factor. JUN synergizes with GLI activator forms by co-occupying selected target gene promoters leading to synergistic transcriptional activation of HH-EGFR targets and enhanced tumorigenesis (e.g., BCC and pancreatic cancer).
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fig0020: Modes of HH-EGF signaling integration. (A) Canonical HH-GLI signaling activated by binding of SHH to its receptor PTCH results in ciliary localization of SMOH and subsequent GLI activation (GLIA). HH-GLI signaling alone only activates classical GLI targets including HHIP and GLI1 but fails to induce HH-EGFR cooperation target genes. (B) Concomitant activation of HH-GLI and EGF/PDGF signaling (EGFR or PDGFRA) can lead to synergistic interactions [46,47]. Such interactions can result in (i) cross talk between SHH and EGFR in neural stem cells [105], (ii) enhancement of GLI1 activity by RAS/MEK signaling in melanomas and other tumor cells [65], and/or (iii) synergistic promotion of basal cell carcinoma and pancreatic cancer by selective activation of HH-EGFR target genes such as CXCR4, FGF19, SOX9 and TGFA [90,92,93]. In the latter case, integration of HH-EGFR signaling occurs at the level of common target gene promoters. Activation of EGF signaling induces the RAS/RAF/MEK/ERK cascade eventually leading to activation of GLI1 or/and of the JUN/AP1 transcription factor. JUN synergizes with GLI activator forms by co-occupying selected target gene promoters leading to synergistic transcriptional activation of HH-EGFR targets and enhanced tumorigenesis (e.g., BCC and pancreatic cancer).

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 [90]. So far, only EGFR and PDGFRA [107] 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].


Context-dependent signal integration by the GLI code: the oncogenic load, pathways, modifiers and implications for cancer therapy.

Aberger F, Ruiz I Altaba A - Semin. Cell Dev. Biol. (2014)

Modes of HH-EGF signaling integration. (A) Canonical HH-GLI signaling activated by binding of SHH to its receptor PTCH results in ciliary localization of SMOH and subsequent GLI activation (GLIA). HH-GLI signaling alone only activates classical GLI targets including HHIP and GLI1 but fails to induce HH-EGFR cooperation target genes. (B) Concomitant activation of HH-GLI and EGF/PDGF signaling (EGFR or PDGFRA) can lead to synergistic interactions [46,47]. Such interactions can result in (i) cross talk between SHH and EGFR in neural stem cells [105], (ii) enhancement of GLI1 activity by RAS/MEK signaling in melanomas and other tumor cells [65], and/or (iii) synergistic promotion of basal cell carcinoma and pancreatic cancer by selective activation of HH-EGFR target genes such as CXCR4, FGF19, SOX9 and TGFA [90,92,93]. In the latter case, integration of HH-EGFR signaling occurs at the level of common target gene promoters. Activation of EGF signaling induces the RAS/RAF/MEK/ERK cascade eventually leading to activation of GLI1 or/and of the JUN/AP1 transcription factor. JUN synergizes with GLI activator forms by co-occupying selected target gene promoters leading to synergistic transcriptional activation of HH-EGFR targets and enhanced tumorigenesis (e.g., BCC and pancreatic cancer).
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fig0020: Modes of HH-EGF signaling integration. (A) Canonical HH-GLI signaling activated by binding of SHH to its receptor PTCH results in ciliary localization of SMOH and subsequent GLI activation (GLIA). HH-GLI signaling alone only activates classical GLI targets including HHIP and GLI1 but fails to induce HH-EGFR cooperation target genes. (B) Concomitant activation of HH-GLI and EGF/PDGF signaling (EGFR or PDGFRA) can lead to synergistic interactions [46,47]. Such interactions can result in (i) cross talk between SHH and EGFR in neural stem cells [105], (ii) enhancement of GLI1 activity by RAS/MEK signaling in melanomas and other tumor cells [65], and/or (iii) synergistic promotion of basal cell carcinoma and pancreatic cancer by selective activation of HH-EGFR target genes such as CXCR4, FGF19, SOX9 and TGFA [90,92,93]. In the latter case, integration of HH-EGFR signaling occurs at the level of common target gene promoters. Activation of EGF signaling induces the RAS/RAF/MEK/ERK cascade eventually leading to activation of GLI1 or/and of the JUN/AP1 transcription factor. JUN synergizes with GLI activator forms by co-occupying selected target gene promoters leading to synergistic transcriptional activation of HH-EGFR targets and enhanced tumorigenesis (e.g., BCC and pancreatic cancer).
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 [90]. So far, only EGFR and PDGFRA [107] 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].

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria. Electronic address: fritz.aberger@sbg.ac.at.

Show MeSH
Related in: MedlinePlus