Mechanisms of protein sequestration at the nuclear periphery. (A) The INM regulates cell stemness via sequestration of Notch, Wnt, and TGFβ pathway effectors. The Notch signaling corepressor NCOR and coactivator SKIP are anchored to the nuclear periphery in normal cells (Zhang et al., 2003; Demmerle et al., 2012). Although NCOR is activated at the nuclear periphery, SKIP may be restricted from binding to Notch-dependent promoters. SKIP has also been shown to interact with SMAD2/3 to regulate TGFβ-dependent transcription (Leong et al., 2001). Similarly, SMAD2/3 is bound to MAN1. The interaction with MAN1 sequesters SMAD2/3, attenuating heterodimerization with Smad4 and suppressing TGFβ-induced transcription (Lin et al., 2005; Pan et al., 2005). Wnt pathway regulation involves emerin-mediated nuclear export of β-catenin as well as the possible stabilization of β-catenin by α-catenin and nuclear actin (Markiewicz et al., 2006; Holaska and Wilson, 2007; Tilgner et al., 2009; Stubenvoll et al., 2015; Serebryannyy et al., 2017). (B) Proliferation is regulated by the interaction of the nuclear lamina with AP-1, Rb, and ERK1/2. Hypophosphorylated cFos and Rb are sequestered by the nuclear lamina, priming a readily available population of transcription factors for rapid cell cycle regulation (González et al., 2008; Rodríguez et al., 2010). Activation and nuclear translocation of ERK1/2 contribute to the phosphorylation of Rb and cFos. Phosphorylated Rb is degraded, freeing E2F to activate transcription. Similarly, phosphorylation of cFos facilitates dimerization with cJun and promoter binding. E2F is also sequestered to the nuclear periphery via its interaction with Germ cell-less (GCL) and Lap2β (Nili et al., 2001). Nuclear ERK1/2 can bind to lamin A/C as well (Rodríguez et al., 2010), potentially regulating its activity and turnover. (C) Lamin A is required for the proper localization and enzymatic activity of SIRT1 and SIRT6, regulating chromatin condensation and poly(ADP-ribose) polymerase 1 (PARP1) activity (Liu and Zhou, 2013; Ghosh et al., 2015). hMOF localization is also dependent on lamin A/C (Füllgrabe et al., 2013), implicating the nuclear lamina in both histone acetylation and deacetylation. In addition, lamin A binds the chromatin remodeling complexes PRC and NuRD, establishing a repressive heterochromatin state at the INM (Pegoraro et al., 2009; Cesarini et al., 2015). (D) The shelterin complex components TRF1/2 and AKTIP regulate telomere replication, length, and stability (Ludérus et al., 1996; Dechat et al., 2004; Wood et al., 2014; Chojnowski et al., 2015). Whereas TRF1 may bind lamin B (Crabbe et al., 2012), TRF2 stabilization of telomeres at the nuclear periphery is dependent on binding to lamin A/C and Lap2α (Chojnowski et al., 2015). Similarly, AKTIP interacts with lamin A/C, lamin B, and PCNA to regulate telomere replication and stability (Burla et al., 2016). The INM-incorporated lipid moiety S1P is also able to promote telomere stability by preventing the degradation of hTERT (Panneer Selvam et al., 2015).