A traffic policeman standing at a busy intersection directing the flow of vehicles may be a rare sight these days, but a similar scene appears to still frequently play out in our cells. A protein called Lem4 directs a crucial step of cell division by preventing the progress of one molecule while waving another through, scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have found. The study is published online in Cell.
For an embryo to grow or a tissue to regenerate, its cells must divide. When one of our cells divides to give rise to two, the membrane that surrounds the cell’s nucleus – the nuclear envelope – has to be broken down and later rebuilt, once the chromosomes have been dragged apart. For this re-assembly to take place, a protein called BAF has to have chemical tags called phosphates removed. Changing a protein’s phosphorylation state – its possession or lack of phosphate tags – can involve regulating the activity of proteins that add phosphate, proteins that remove phosphate, or both. The EMBL scientists discovered a new molecule, Lem4, which acts as a traffic policeman, stopping one protein from adding phosphate tags to BAF and bringing in another protein to remove the existing tags.
“This happens in both human cells and in the worm C. elegans, so it seems to be a strategy which evolved long ago,” says Iain Mattaj, director-general of EMBL, who led the work.
Through a combination of genetics and biochemical studies, the scientists found that, even though the worm version of Lem4 is markedly different from the human version, both perform the same double task at the end of cell division. Mattaj and colleagues suspect that this tactic – having a single molecule that prevents tags being added and simultaneously promotes their removal – could be employed in the many cellular processes that involve phosphate tags, such as the growth and division of cells or transmitting signals into cells from the environment.
It would now be interesting to investigate just what prompts Lem4 to start its double-action at the right moment, they say.
Mitosis in metazoa requires nuclear envelope (NE) breakdown and reassembly. Multiple phosphorylation events drive NE disassembly but how dephosphorylation is regulated to enable reassembly is almost entirely unknown. Here, we report that Lem4 is required for the function of both a mitotic kinase and a phosphatase that act on BAF, an essential effector of nuclear assembly. Lem4 is required for dephosphorylation of BAF by inhibiting its mitotic kinase, VRK-1, in vivo and in vitro. In addition, Lem4 interacts with PP2A and is required for it to dephosphorylate BAF during mitotic exit. By coordinating VRK-1 and PP2A mediated signaling on BAF, Lem4 controls postmitotic NE formation in a function conserved from worms to humans.
Asencio, C., Davidson, I. F., Santarella-Mellwig, R., Ly-Hartig, T.B.N., Mall, M., Wallenfang, M.R., Mattaj, I.W. & Gorjánácz, M. Coordination of Kinase and Phosphatase Activities by Lem4 Enables Nuclear Envelope Reassembly during Mitosis Cell, 6 July 2012.
European Molecular Biology Laboratory