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The role of Rab11-FIP3 and Rab11-FIP4 in cytokinesis

Reference	BB/D000017/1
Principal Investigator / Supervisor	Professor Gwyn William Gould
Co-Investigators / Co-Supervisors	Dr J Matheson
Institution	University of Glasgow
Department	School of Life Sciences
Funding type	Research
Value (£)	361,742
Status	Completed
Type	Research Grant
Start date	12/08/2005
End date	11/11/2009
Duration	51 months

Abstract

Cytokinesis is the terminal step of the cell cycle that results in the cleavage of the mother cell into two daughter cells. Studies of cytokinesis have clearly shown that the surface area of the dividing cells increases through cytokinesis. This increase is not a consequence of the expansion of the existing plasma membrane, but rather is accomplished, at least in part, by the delivery of new membrane to the cell surface. Consistent with this, numerous studies have shown that this new plasma membrane has composition distinct from the existing plasma membrane, and likely arises by the delivery of internal membrane to the growing furrow. Intracellular stores of membrane from the secretory or recycling endosomal system are obvious candidates for this new membrane addition. My laboratory has recently shown that Rab11-positive endosomes traffic into the furrow of dividing cells during cytokinesis, and that depletion of Rab11 or perturbation of Rab11 function results in defective cytokinesis and delayed abscission. We have further shown that the class II Rab11 family of interacting proteins (FIP3 and FIP4) are required for cytokinesis in mammalian cells. These two proteins have been extensively characterised by my laboratory and we have shown that these proteins directly bind both Rab11 and Arf6 at distinct sites. Moreover, FIP3 and FIP4 exhibit unique spatial regulation during the cell cycle. FIP3 is found to decorate Rab11-positive endosomes in the furrow and appear late in the midbody during late telophase. FIP4 decorates the spindle microtubules before concentrating in the midbody. Depletion of FIP3 using siRNA results in aberrant cytokinesis. Based upon a large body of data (see main text of the proposal), we offer the following model for membrane traffic during cytokinesis: FIP3 binds via Rab11 to vesicles derived from recycling endosomes. During anaphase, these vesicles are mobilised to the furrow via recruitment onto microtubules at the centrosome, and FIP4-containing structures are localised onto spindle microtubules, presumably also for delivery into the furrow region. Upon arrival at the plasma membrane of the furrow (and later in the midbody) interaction with Arf6 facilitates interaction, perhaps via the Exocyst, prior to fusion. The fusion of vesicles with the plasma membrane results in the delivery of additional membrane area to the surface of dividing cells, and the arrival at the furrow of important, but presently unidentified, cargo. Finally, we propose that FIP3/4 dependent delivery of cargo deep in the midbody is essential for the terminal step of cytokinesis - abscission. The objective of this proposal is to test specific aspects of this hypothesis and thus further our understanding of the control of cell division.

Summary

Cytokinesis is the terminal step of the cell cycle that results in the cleavage of the mother cell into two daughter cells. During this event, cells undergo characteristic shape changes. Firstly, the cell rounds up and then elongates into a cylindrical shape structure. A furrow forms around the equator of the cell and begins to ingress, maintaining continuous curvature with the cortex. At later stages, a distinct bridge forms between the cells which elongates, thins and eventually is severed during the terminal step - abscission. As cells divide, their surface area increases. This is not a consequence of expansion of the existing plasma membrane, but rather the cell moves internal membrane stores to the plasma membrane to accommodate both the shape change and increased surface area. We are studying the mechanism of this movement of internal membrane (vesicle) stores. Our hypothesis is that these membrane stores deliver important cargo to the cell surface, in addition to fulfilling the role of increasing membrane area. Hence, understanding this process is of fundamental importance to developing a complete picture of the control of cell division. We seek to understand how the vesicles move, what controls this movement and what the vesicles take with them.

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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