The response shuts off when Ca2+ levels decrease, releasing nf-aT from calcineurin. rephosphorylation of nf-aT inactivates the nuclear import signals and re-exposes the nuclear export signal, causing nf-aT to relocate to the cytosol. some of the most potent immunosuppressive drugs, including cyclosporin a and fK506, inhibit the ability of calcineurin to dephosphorylate nf-aT and thereby block the nuclear accumulation of nf-aT and T cell activation (Movie 12.1).
During mitosis the nuclear envelope Disassembles
The nuclear lamina, located on the nuclear side of the inner nuclear membrane, is a meshwork of interconnected protein subunits called nuclear lamins. The lamins are a special class of intermediate filament proteins (discussed in Chapter 16) that polymerize into a two-dimensional lattice (Figure 12–17). The nuclear lamina gives shape and stability to the nuclear envelope, to which it is anchored by attachment to both the NPCs and transmembrane proteins of the inner nuclear membrane. The lamina also interacts directly with chromatin, which itself interacts with transmembrane proteins of the inner nuclear membrane. Together with the lamina, these inner membrane proteins provide structural links between the DNA and the nuclear envelope.
When a nucleus is dismantled during mitosis, the NPCs and nuclear lamina disassemble and the nuclear envelope fragments. The dismantling process is at least partly a consequence of direct phosphorylation of nucleoporins and lamins by the cyclin-dependent protein kinase (Cdk) that is activated at the onset of mitosis (discussed in Chapter 17). During this process, some NPC proteins become bound to nuclear import receptors, which play an important part in the reassembly of NPCs at the end of mitosis. Nuclear envelope membrane proteins—no longer tethered to the pore complexes, lamina, or chromatin—disperse throughout the ER membrane. The dynein motor protein, which moves along microtubules (discussed in Chapter 16), actively participates in tearing the nuclear envelope off the chromatin. Together, these processes break down the barriers that normally separate the nucleus and cytosol, and the nuclear proteins that are not bound to membranes or chromosomes intermix completely with the proteins of the cytosol (Figure 12–18).
Later in mitosis, the nuclear envelope reassembles on the surface of the daughter chromosomes. In addition to its crucial role in nuclear transport, the Ran GTPase also acts as a positional marker for chromatin during cell division, when the nuclear and cytosolic components intermix. Because Ran-GEF remains bound to chromatin when the nuclear envelope breaks down, Ran molecules close to chromatin are mainly in their GTP-bound conformation. By contrast, Ran molecules further away have a high likelihood of encountering Ran-GAP, which is distributed throughout the cytosol; these Ran molecules are mainly in their GDP-bound conformation. As a result, the chromosomes in mitotic cells are surrounded by a cloud of Ran-GTP. Ran-GTP releases the NPC proteins in proximity to the chromosomes from nuclear import receptors. The free NPC proteins attach