Project Details
Projekt
Characterisation of Individual Functions of Cdc42 Isoforms in Cellular Processes and Glioblastoma Progression
Applicant
Dr. Jan Hänisch
Subject Area
Cell Biology
Term
from 2011 to 2012
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 194096189
The Rho-GTPase Cdc42 is a key regulator of actin microfilaments and microtubules. Consequently, Cdc42 plays a crucial role in the control of cell behaviour, including polarization and motility and also cellular membrane traffic. Changes in Cdc42 activity are thus likely to affect the invasive properties of cancer cells and to play a role in tumour progression. Two isoforms of Cdc42 exist. The first one is ubiquitously expressed and the second is brain-specific. Most studies have focused on the former and the specific functions of the brain-specific isoform remain obscure. Interestingly, unpublished observations by the Etienne-Manneville lab uncover a strong down-regulation of the ubiquitous Cdc42 isoform in astrocyte-derived glioblastoma, leaving the brain-specific isoform as the only Cdc42 variant significantly expressed in these tumour cells. Unravelling the functional differences between the two isoforms is thus essential to better understand Cdc42-regulated processes and to determine the consequences of changes in Cdc42 expression in glioblastoma. The two Cdc42 variants differ within the carboxy terminal CAAX box, a site of posttranslational lipid tail addition, which controls the cellular targeting of Rho-GTPases. The proposed work includes a comparison of lipid modifications and intracellular localization of the two variants. The capacity of each isoform to interact with known Cdc42 binding partners will be assessed, as well as the ability to regulate particular aspects of actin and microtubule dynamics. How isoform-specific alterations of Cdc42 expression may affect membrane protrusion, cell polarization, cell motility and endocytosis will be explored in normal astrocytes, the behaviour of which will then be compared to that of glioblastoma cells. Finally, the ubiquitous isoform of Cdc42 will be exogenously expressed in glioblastoma cells to confirm that its loss contributes to the abnormal behaviour of tumorous astrocytes.
DFG Programme
Research Fellowships
International Connection
France
