Human Molecular Genetics Advance Access originally published online on July 29, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Human Molecular Genetics, 2003, Vol. 12, No. 19 2449-2456
DOI: 10.1093/hmg/ddg250
© 2003 Oxford University Press
Lowe syndrome protein OCRL1 interacts with Rac GTPase in the trans-Golgi network
1Institut Cochin, Département de Génétique, Développement et Pathologie Moléculaire, INSERM U567/CNRS UMR8104/Université Paris V, 24 rue du Faubourg Saint Jacques, 75014 Paris, France and 2Laboratoire de Biochimie de l'ADN, EA 2943 MENRT-CEA, CHU Grenoble, 38043 Grenoble, France
Received May 6, 2003; Revised June 19, 2003; Accepted July 21, 2003
The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked disorder characterized by severe mental retardation, congenital cataracts and renal Fanconi syndrome. OCRL1 protein is a phosphatidylinositol 4,5-bisphosphate 5-phosphatase with a C-terminal RhoGAP domain. Considering the pleiotropic cellular functions of Rho GTPases (Rho, Rac and Cdc42) and their dysregulation in several forms of mental retardation, we have investigated the so far unexplored function of the RhoGAP domain of OCRL1. Activated Rac GTPase was found to stably associate with the OCRL1 RhoGAP domain in vitro and to co-immunoprecipitate with endogenous OCRL1. Contrasting with other GAPs, OCRL1 RhoGAP exhibited a significant interaction with GDP bound Rac in vitro. As compared to Rac, other Rho GTPases tested showed reduced (Cdc42) or no binding (RhoA, RhoG) to OCRL1 RhoGAP. Immunofluorescence studies in HEK and COS7 cells and Golgi perturbation assays with Brefeldin A demonstrated that a fraction of endogenous Rac co-localizes with OCRL1 and 
-adaptin in the trans-Golgi network. The OCRL1 RhoGAP domain showed low Rac GAP activity in vitro, and when expressed in Swiss 3T3 cells induced specific inhibition of RacGTP dependent ruffles, consistent with OCRL1 being an active RacGAP. OCRL1 appears to be a bifunctional protein which, in addition to its PIP2 5-phosphatase activity, binds to Rac GTPase. This novel property may play a role in localizing OCRL1 to the trans-Golgi network. Moreover, loss of OCRL1 RhoGAP and the resulting alteration in Rho pathways may contribute to mental retardation in Lowe syndrome, as illustrated in other forms of X-linked mental retardation.
* To whom correspondence should be addressed. Tel: +33 144412470; Fax: +33 144412448; Email: gacon{at}cochin.inserm.fr
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  B. G. Coon, D. Mukherjee, C. B. Hanna, D. J. Riese II, M. Lowe, and R. C. Aguilar Lowe syndrome patient fibroblasts display Ocrl1-specific cell migration defects that cannot be rescued by the homologous Inpp5b phosphatase Hum. Mol. Genet., December 1, 2009; 18(23): 4478 - 4491. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Choudhury, C. J. Noakes, E. McKenzie, C. Kox, and M. Lowe Differential Clathrin Binding and Subcellular Localization of OCRL1 Splice Isoforms J. Biol. Chem., April 10, 2009; 284(15): 9965 - 9973. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Williams, R. Choudhury, E. McKenzie, and M. Lowe Targeting of the type II inositol polyphosphate 5-phosphatase INPP5B to the early secretory pathway J. Cell Sci., November 15, 2007; 120(22): 3941 - 3951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-Y. Yoon, K. Miura, E. J. Cuthbert, K. K. Davis, B. Ahvazi, J. E. Casanova, and P. A. Randazzo ARAP2 effects on the actin cytoskeleton are dependent on Arf6-specific GTPase-activating-protein activity and binding to RhoA-GTP J. Cell Sci., November 15, 2006; 119(22): 4650 - 4666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Faucherre, P. Desbois, F. Nagano, V. Satre, J. Lunardi, G. Gacon, and O. Dorseuil Lowe syndrome protein Ocrl1 is translocated to membrane ruffles upon Rac GTPase activation: a new perspective on Lowe syndrome pathophysiology Hum. Mol. Genet., June 1, 2005; 14(11): 1441 - 1448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Rangel-Filho, M. Sharma, Y. H. Datta, C. Moreno, R. J. Roman, Y. Iwamoto, A. P. Provoost, J. Lazar, and H. J. Jacob Rf-2 Gene Modulates Proteinuria and Albuminuria Independently of Changes in Glomerular Permeability in the Fawn-Hooded Hypertensive Rat J. Am. Soc. Nephrol., April 1, 2005; 16(4): 852 - 856. [Full Text] [PDF]
|
|
|
|
 |
|
 E.-E. Govek, S. E. Newey, and L. Van Aelst The role of the Rho GTPases in neuronal development Genes & Dev., January 1, 2005; 19(1): 1 - 49. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Zhong, D. H. Burk, W. H. Morrison III, and Z.-H. Ye FRAGILE FIBER3, an Arabidopsis Gene Encoding a Type II Inositol Polyphosphate 5-Phosphatase, Is Required for Secondary Wall Synthesis and Actin Organization in Fiber Cells PLANT CELL, December 1, 2004; 16(12): 3242 - 3259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Morales-Johansson, P. Jenoe, F. T. Cooke, and M. N. Hall Negative Regulation of Phosphatidylinositol 4,5-Bisphosphate Levels by the INP51-associated Proteins TAX4 and IRS4 J. Biol. Chem., September 17, 2004; 279(38): 39604 - 39610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A.J. Devonald and F. E. Karet Renal Epithelial Traffic Jams and One-Way Streets J. Am. Soc. Nephrol., June 1, 2004; 15(6): 1370 - 1381. [Full Text] [PDF]
|
|