What MAN1 does to the smads - TGF beta/BMP signaling and the nuclear envelope

The inner nuclear membrane protein MAN1 has been identified as an important factor in transforming growth factor beta/bone morphogenic protein (TGF beta/BMP) signaling. Loss of MAN1 results in three autosomal dominant diseases in humans; all three characterized by increased bone density. Xenopus embryos lacking MAN1 develop severe morphological defects. Both in humans and in Xenopus embryos the defects originate from deregulation of TGF beta/BMP signaling. Several independent studies have shown that MAN1 is antagonizing TGF beta/BMP signaling through binding to regulatory Smads. Here, recent progress in understanding MAN1 functions is summarized and a model for MAN1-dependent regulation of TGF beta/BMP signaling is proposed.