ayout 1 - EMBL Grenoble

Directors’ Research
The RanGTPase as a spatial regulator
Previous and current research
The research in our group is centred on diverse processes that are under the control of the Ran GT-
Pase. Ran requires regulators for its activity. These are a GEF (Guanine Nucleotide Exchange Factor)
that loads Ran with GTP, and a GAP (GTPase Activating Protein) that is required for Ran to
hydrolyse GTP to GDP. These two factors are asymmetrically distributed within cells, both in interphase
and during mitosis (see figure). As a result, RanGTP is present in interphase at high concentration
in the nucleus and at low concentration in the cytoplasm. In mitosis, RanGTP
production is locally increased in the vicinity of chromatin because of the concentration of the
GEF there. RanGTP interacts with the import and export receptors that mediate nucleo-cytoplasmic
transport. In the former case, this interaction results in import cargo release. Thus, import
receptors bind cargo in the cytoplasm (low Ran GTP) and release it in the nucleus (high RanGTP).
Ran’s effect on export receptors is the opposite, they only interact with their cargoes in the presence
of RanGTP. These RanGTP-dependent binding events impart directionality to nuclear transport.
During mitosis, Ran is needed for both mitotic spindle assembly and nuclear envelope (NE)
formation (see figure). Remarkably, our studies suggest that Ran’s mitotic functions occur by the
same mechanism as nucleo-cytoplasmic transport, i.e. via regulation of interactions between transport
receptors and factors involved in spindle or NE assembly.
Iain Mattaj
PhD 1979, University of
Leeds.
Postdoctoral work at the
Friedrich Miescher Institute
and the Biocenter, Basel.
Group leader at EMBL since
1985. Programme
Coordinator since 1990.
Scientific Director of EMBL
1999–2005. Director General
since 2005.
Future projects and goals
In the case of spindle formation, we know that Ran regulates multiple aspects of spindle assembly; microtubule nucleation, microtubule stability,
the production of anti-parallel microtubule arrays, the focussing of the spindle poles, etc. We are using in vitro and in vivo methods to
identify the factors that mediate these processes and to find out how they function and how Ran controls their activity.
NE assembly is a multi-stage process. Both the membranes that give rise to the NE and the proteins that form nuclear pore complexes (NPCs),
through which transport across the NE occurs, associate with the chromatin surface early in NE assembly. Membrane fusion events and NPC
assembly proceed in concert, and have to be regulated in an integrated way. We have begun to understand how Ran controls NPC assembly
but we have essentially no information
on how the NE membranes assemble, or
how NPC insertion into the membranes
takes place. In addition, although we
know that Ran regulates where NE assembly
occurs in the cell, we do not
know how the process is temporally regulated,
i.e. why it occurs in telophase
rather than in metaphase. Understanding
the spatial regulation of mitotic
events by Ran and their temporal regulation
during the cell cycle is an ambitious
long-term goal.
The local production of RanGTP, caused
by the non-uniform distribution of the Ran
GEF and Ran GAP in relation to the
nuclear envelope or the chromosomes at
various stages in the cell cycle.
Selected references
Galy, V., Antonin, W., Jaedicke, A., Sachse, M., Santarella, R.,
Haselmann, U. & Mattaj, I. (2008). A role for gp210 in mitotic nuclearenvelope
breakdown. J. Cell Sci., 121, 317-328
Franz, C., Walczak, R., Yavuz, S., Santarella, R., Gentzel, M.,
Askjaer, P., Galy, V., Hetzer, M., Mattaj, I.W. & Antonin, W. (2007).
MEL-28/ELYS is required for the recruitment of nucleoporins to
chromatin and postmitotic nuclear pore complex assembly. EMBO
Rep., 8, 165-172
Gorjanacz, M., Klerkx, E.P., Galy, V., Santarella, R., Lopez-Iglesias,
C., Askjaer, P. & Mattaj, I.W. (2007). Caenorhabditis elegans BAF-1
and its kinase VRK-1 participate directly in post-mitotic nuclear
envelope assembly. EMBO J., 26, 132-13
Galy, V., Askjaer, P., Franz, C., Lopez-Iglesias, C. & Mattaj, I.W.
(2006). MEL-28, a novel nuclear-envelope and kinetochore protein
essential for zygotic nuclear-envelope assembly in C. elegans. Curr.
Biol., 16, 178-1756
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