Signaling at the Nuclear Envelope

Publisher Summary This chapter focuses on the role that inner nuclear membrane (INM) proteins and lamins play in cellular signaling pathways and explains the cellular regulatory functions of nuclear pore complexes (NPC) proteins. Most INM proteins interact with lamins and/or chromatin, making them relatively resistant to Triton extraction and immobile in fluorescence recovery after photobleaching (FRAP) analysis. The NE transmembrane proteins MAN1 and Dullard/NET56 act as regulators of transforming growth factor β (TGFβ)/bone morphogenic protein (BMP) signaling. Another NE protein that participates in BMP signaling is Dullard/NET56 that impairs BMP signaling through binding to BMP receptors and promoting their proteosomal degradation via the lipid raft-caveolar pathway. Dullard/NET56 is implicated in insulin signaling through the dephosphorylation of lipin, a mammalian phosphatidic acid phosphatase. Lipin is required for normal adipose tissue development and is central to nuclear membrane biogenesis and lipid signaling. Phosphorylation and localization of lipin is in part regulated by insulin. Proteins of the retinoblastoma protein (pRB) family repress gene expression from E2F responsive promoters. Hyperphosphorylation of pRB by cyclin dependent kinases (CDKs) releases suppression and allows the cells to transition from G 1 phase into S-phase. In addition to cell cycle progression, pRB also controls numerous cellular events such as DNA repair, apoptosis, and differentiation. Nuclear factor кB (NFкB) is a key regulator of both adaptive and innate immune responses. It acts as an antiapoptotic transcription factor contributing to cell survival and metastatic potential. The expression from an NFкB activated reporter gene is significantly impaired in the LMNA -/- cells under mechanical stress and there is an increase in the proportion of both apoptotic and necrotic cells.