Integrins are heterodimeric transmembrane adhesion receptors that couple the actin cytoskeleton to the extracellular environment and bidirectionally relay signals across the cell membrane. These processes are critical for cell attachment, migration, differentiation, and survival, and therefore play essential roles in metazoan development, physiology, and pathology. Integrin-mediated adhesions are regulated by diverse factors, including the conformation-specific affinities of integrin receptors for their extracellular ligands, the clustering of integrins and their intracellular binding partners into discrete adhesive structures, mechanical forces exerted on the adhesion, and the intracellular trafficking of integrins themselves. Recent advances shed light onto how the interaction of specific intracellular proteins with the short cytoplasmic tails of integrins controls each of these activities.

Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumor syndrome that includes susceptibility to pancreatic islet tumors. This syndrome results from mutations in the MEN1 gene, encoding menin. Menin acts as an oncogenic co-factor for MLL-fusion protein-mediated histone H3 lysine 4 methylation, but the precise basis for how menin suppresses gene expression and proliferation of pancreatic beta cells remains poorly understood. Here we show that menin ablation enhances Hedgehog (Hh) signaling, a pro-proliferative and oncogenic pathway, in murine pancreatic islets. Menin directly interacts with protein arginine methyltransferase 5 (PRMT5), a negative regulator of gene transcription. Menin recruits PRMT5 to the promoter of the Gas1 gene, a crucial factor for binding of Sonic hedgehog (Shh) ligand to its receptor PTCH1 and subsequent activation of the Hh signaling pathway, increases repressive histone arginine dimethylation (H4R3m2s) and suppresses Gas1 expression. Notably, MEN1 disease-related menin mutants have reduced binding to PRMT5, and fail to impart the repressive H4R3m2s mark at the Gas1 promoter, resulting in its elevated expression. Pharmacological inhibition of Hh signaling significantly reduces proliferation of insulinoma cells, and expression of Hh signaling targets including Ptch1, in MEN1 tumors of mice. These findings uncover a novel link between menin and Hh signaling whereby menin/PRMT5 epigenetically suppress Hh signaling, revealing it as a target for treating MEN1 tumors.