Abstract
Understanding transcription factor navigation through the nucleus remains critical for developing targeted therapeutics. The GLI1 transcription factor must maintain maximal Hedgehog pathway output in basal cell carcinomas (BCCs), and we have previously shown that resistant BCCs increase GLI1 deacetyla- tion through atypical protein kinase Ci/l (aPKC) and HDAC1. Here we identify a lamina-associated polypeptide 2 (LAP2) isoform-dependent nuclear chaperoning system that regulates GLI1 movement between the nuclear lamina and nucleoplasm to achieve maximal activation. LAP2b forms a two-site interaction with the GLI1 zinc-finger domain and acetylation site, stabilizing an acetylation-dependent reserve on the inner nuclear membrane (INM). By contrast, the nucleoplasmic LAP2a competes with LAP2b for GLI1 while scaffolding HDAC1 to deacety- late the secondary binding site. aPKC functions to pro- mote GLI1 association with LAP2a, promoting egress off the INM. GLI1 intranuclear trafficking by LAP2 iso- forms represents a powerful signal amplifier in BCCs with implications for zinc finger-based signal trans- duction and therapeutics.
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