Summary The Merlin/NF2 tumor suppressor restrains cell growth and tumorigenesis by controlling contact-dependent inhibition of proliferation. We have identified a tight-junction-associated protein complex comprising Merlin, Angiomotin, Patj, and Pals1. We demonstrate that Angiomotin functions downstream of Merlin and upstream of Rich1, a small GTPase Activating Protein, as a positive regulator of Rac1. Merlin, through competitive binding to Angiomotin, releases Rich1 from the Angiomotin-inhibitory complex, allowing Rich1 to inactivate Rac1, ultimately leading to attenuation of Rac1 and Ras-MAPK pathways. Patient-derived Merlin mutants show diminished binding capacities to Angiomotin and are unable to dissociate Rich1 from Angiomotin or inhibit MAPK signaling. Depletion of Angiomotin in Nf2−/− Schwann cells attenuates the Ras-MAPK signaling pathway, impedes cellular proliferation in vitro and tumorigenesis in vivo.

Rhythmic changes in histone acetylation at circadian clock genes suggest that temporal modulation of gene expression is regulated by chromatin modifications1-3. Furthermore, recent studies demonstrate a critical relationship between circadian and metabolic physiology4-7. The Nuclear Receptor Co-Repressor 1 (NCoR) functions as an activating subunit for the chromatin modifying enzyme histone deacetylase 3 (HDAC3)8. Lack of NCoR is incompatible with life, and hence it is unknown whether NCoR, and particularly its regulation of HDAC3, is critical for adult mammalian physiology9. Here we show that specific, genetic disruption of the NCoR-HDAC3 interaction in mice causes aberrant regulation of clock genes and results in abnormal circadian behavior. These mice are also leaner and more insulin sensitive due to increased energy expenditure. Unexpectedly, loss of a functional NCoR-HDAC3 complex in vivo does not lead to sustained elevations of known catabolic genes, but rather significantly alters the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. These findings indicate that activation of HDAC3 by NCoR is a nodal point in the epigenetic regulation of circadian and metabolic physiology.Mammals display circadian rhythms in behavioral and physiologic processes, such as sleep, feeding, blood pressure, and metabolism10-12, guided by external light-dark signals that are integrated through intrinsic central and peripheral molecular clocks13, 14. Several critical clock and clock output genes display daily cycling of histone acetylation, suggesting that epigenetic regulation of chromatin plays a central role in circadian regulation1-3. Nuclear Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use

K-ras is the most commonly mutated oncogene in pancreatic cancer and its activation in murine models is sufficient to recapitulate the spectrum of lesions seen in human pancreatic ductal adenocarcinoma