Abstract
Hedgehog (Hh) pathway plays a pivotal role in diverse aspects of development and postnatal physiology. Perturbation of Hh signaling and activation of GLI1 (glioma-associated oncogene 1), a dedicated transcription factor for Hh pathway, are highly associated with several cancers, such as medulloblastoma and basal cell carcinoma. Dynamic and precise control of GLI1 activity is thus important to ensure proper homeostasis and tumorigenesis. Here we show that MEKK2 (MAP3K2) and MEKK3 (MAP3K3) inhibit GLI1 transcriptional activity and oncogenic function through phosphorylation on multiple Ser/Thr sites of GLI1, which reduces GLI1 protein stability, DNA-binding ability, and increases the association of GLI1 with SUFU. Interestingly, MEKK2 and MEKK3 are responsible for FGF2-mediated inhibition on Hh signaling. Moreover, expression of MEKK2 and MEKK3 inhibits medulloblastoma cell proliferation and negatively correlates with Hh pathway activity in medulloblastoma clinical samples. Together, these findings reveal a novel noncanonical GLI1 regulation and provide a potential therapeutic target for the treatment of cancers with aberrant Hh pathway activation, such as medulloblastoma.
Highlights
Hedgehog (Hh) signaling is highly conserved from Drosophila to mammals and plays a crucial role in many aspects of embryonic development, such as neural tube and limb patterning in vertebrates [1,2,3]
We found that MEKK2 and MEKK3 displayed the most significant suppressive activity on GliBS-Luc reporter
Control of GLI1 expression is critical for cell proliferation and its abnormal regulation leads to tumor progression
Summary
Hedgehog (Hh) signaling is highly conserved from Drosophila to mammals and plays a crucial role in many aspects of embryonic development, such as neural tube and limb patterning in vertebrates [1,2,3]. Hh signaling transduction is initiated through ligand binding and inactivating the Hh receptor PTCH1. This relieves PTCH1 repression on the seven-pass transmembrane protein Smoothened (SMO) and enables SMO to translocate to the cilium tip, driving a signaling cascade that culminates in the production of glioma-associated oncogene (GLI) activators. GLI3 repressor generated by proteolysis silences Hh target gene expression in the Relative luciferase activity pCDNA3 MEKK3 MEKK2
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