PRINCIPAL SCIENTIST
 Gascard, P

 STUDENTS
Lu, W
Liou, A

 STAFF
 Calinisan, V

 

My long-term interest concerns the structure and the function
of a family of cytoskeletal proteins called 4.1 proteins.

 

Their prototypical member, protein 4.1R, has been initially characterized in red blood cells, in which this protein confers upon red blood cells their mechanical properties. Protein 4.1R has been also identified in nucleated cells where it adopts a broad distribution including the nucleus, the centrosome, the mitotic apparatus, the microtubules, the plasma membrane and possibly the Golgi apparatus.

This broad distribution likely results from two facts. First, the protein 4.1R gene is subject to a very complex alternative splicing of its pre-MRNA, which results in generation of a panel of isoforms from a single gene. This splicing has been shown to be tissue specific and developmentally-regulated. Second, three genes, highly homologous to 4.1R, and named 4.1G, 4.1N and 4.1B, have been recently characterized.

My project is aimed at defining the structure and function of the 4.1 family of proteins in kidney, a tissue of choice for such studies since its physiology has been very extensively investigated. Three 4.1 proteins, 4.1R, 4.1B and 4.1N are expressed in kidney where they adopt specific and mutually exclusive localization, an observation which strongly suggests specific functions for each protein in kidney. 4.1R null mice, generated in our laboratory, show a potential renal phenotype, supporting an important role of 4.1 proteins in kidney function. There is increasing evidence for mislocalization and decrease in level of expression of various transmembrane proteins, including ion transporters, in various tissues when expression of 4.1 proteins is decreased, an observation which could explain the phenotype observed in kidney. Another recent and exciting discovery is that, at least the three 4.1 proteins identified in kidney, 4.1R, 4.1B and 4.1N act as tumor suppressers.

The aims of studies performed in our laboratory and through collaborations outside of LBNL are a) to identify the region in 4.1 proteins responsible for their anti-proliferative properties and b) to decipher the 4.1 protein-dependent transduction pathways involved in control of cell proliferation. Therefore, 4.1 proteins end up not being only structural proteins but also representing key players in major cell functions. The extensive identification of 4.1 protein binding partners, currently under way, will be in that respect a tremendous boost in the understanding of the roles of these fascinating proteins.

Philippe Gascard
Staff Scientist/
Life Sciences Division

One Cyclotron Rd.
Mailstop: 74-157
Berkeley, CA 94720
tel: (510)486-7587
fax: (510)486-6746
email: PDGascard@lbl.gov
 

 

Walensky LD, Gascard P, Fields ME, Blackshaw S, Conboy JG, Mohandas N, and Snyder SH. The 13-kD FK506 binding protein, FKBP13, interacts with a novel homologue of the erythrocyte membrane cytoskeletal protein 4.1. J. Cell. Biol. 1998. 141:143-153.

Gascard P, Lee G, Coulombel L, Auffray I, Lum M, Parra M, Conboy JG, Mohandas N, and Chasis JA. Characterization of multiple isoforms of protein 4.1R expressed during erythroid terminal differentiation. Blood 1998. 92:4404-4414.

Walensky LD, Shi ZT, Blackshaw S, DeVries AC, Demas GE, Gascard P, Nelson RJ, Conboy JG, Rubin E, Snyder, SH, and Mohandas N. Focal neurobehavioral deficits in mice lacking the erythrocyte membrane cytoskeletal protein 4.1. Curr. Biol. 1998. 8:1269-1272.

Gascard P, Nunomura W, Lee G, Walensky LD, Krauss SW, Chasis JA, Mohandas N, and Conboy JG. Deciphering the nuclear import pathway for the cytoskeletal protein 4.1R. Mol. Biol. Cell 1999. 10:1783-1798.

Mohandas N, and Gascard P. What do mouse gene knockouts tell us about the structure and function of the red cell membrane ? Bailliers Best Pract. Res. Clin. Haematol. 1999 12:605-620. (book chapter)

Parra M, Gascard P, Walensky LD, Gimm JA, Blackshaw S, Chan N, Takakuwa Y, Berger T, Lee G, Chasis JA, Snyder SH, Mohandas N, and Conboy JG. Molecular and functional characterization of protein 4.1B, a novel member of the protein 4.1 family with high level, focal expression in brain. J. Biol. Chem. 2000, 275:3247-3255.

Gascard P, and Narla M. New insights into functions of erythroid proteins in nonerythroid cells. Curr. Opin. Hematol. 2000, 7:123-129. (review)

An XL, Takakuwa Y, Manno S, Han BG, Gascard P, and Mohandas N. Structural and functional characterization of protein 4.1R-phosphatidylserine interaction: potential role in 4.1R sorting within cells. J. Biol. Chem. 2001, 276:35778-35785.

Ramez M, Blot-Chabaud M, Cluzeaud F, Chanan S, Patterson M, Walensky LD, Marfatia S, Baines AJ, Chasis JA, Conboy JG, Mohandas N, and Gascard P. Distinct distribution of specific members of protein 4.1 gene family in the mouse nephron. Kidney Int. 2003. 63:1321-1337.

Robb VA, Li W, Gascard P, Perry A, N Mohandas, and Gutmann DH. Identification of a third Protein 4.1 tumor suppressor, Protein 4.1R, in meningioma pathogenesis. Neurobiol Dis. (in press).