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Wolverhampton Intellectual Repository and E-Theses > Research Institutes > Research Institute in Healthcare Science > Molecular Pharmacology Research Group > Novel functional interaction between the plasma membrane Ca2+ pump 4b and the proapoptotic tumor suppressor Ras-associated factor 1 (RASSF1).

Please use this identifier to cite or link to this item: http://hdl.handle.net/2436/7698
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Title: Novel functional interaction between the plasma membrane Ca2+ pump 4b and the proapoptotic tumor suppressor Ras-associated factor 1 (RASSF1).
Authors: Armesilla, Angel Luis
Williams, Judith C.
Buch, Mamta H.
Pickard, Adam
Emerson, Michael
Cartwright, Elizabeth J.
Oceandy, Delvac
Vos, Michele D.
Gillies, Sheona
Clark, Geoffrey J.
Neyses, Ludwig
Citation: J. Biol. Chem. 2004, 279(30):31318-28
Publisher: American Society for Biochemistry and Molecular Biology
Issue Date: 2004
URI: http://hdl.handle.net/2436/7698
DOI: 10.1074/jbc.M307557200
PubMed ID: 15145946
Additional Links: http://www.jbc.org/cgi/reprint/279/30/31318
Abstract: Plasma membrane calmodulin-dependent calcium ATPases (PMCAs) are enzymatic systems implicated in the extrusion of calcium from the cell. We and others have previously identified molecular interactions between the cytoplasmic COOH-terminal end of PMCA and PDZ domain-containing proteins. These interactions suggested a new role for PMCA as a modulator of signal transduction pathways. The existence of other intracellular regions in the PMCA molecule prompted us to investigate the possible participation of other domains in interactions with different partner proteins. A two-hybrid screen of a human fetal heart cDNA library, using the region 652-840 of human PMCA4b (located in the catalytic, second intracellular loop) as bait, revealed a novel interaction between PMCA4b and the tumor suppressor RASSF1, a Ras effector protein involved in H-Ras-mediated apoptosis. Immunofluorescence co-localization, immunoprecipitation, and glutathione S-transferase pull-down experiments performed in mammalian cells provided further confirmation of the physical interaction between the two proteins. The interaction domain has been narrowed down to region 74-123 of RASSF1C (144-193 in RASSF1A) and 652-748 of human PMCA4b. The functionality of this interaction was demonstrated by the inhibition of the epidermal growth factor-dependent activation of the Erk pathway when PMCA4b and RASSF1 were co-expressed. This inhibition was abolished by blocking PMCA/RASSSF1 association with an excess of a green fluorescent protein fusion protein containing the region 50-123 of RASSF1C. This work describes a novel protein-protein interaction involving a domain of PMCA other than the COOH terminus. It suggests a function for PMCA4b as an organizer of macromolecular protein complexes, where PMCA4b could recruit diverse proteins through interaction with different domains. Furthermore, the functional association with RASSF1 indicates a role for PMCA4b in the modulation of Ras-mediated signaling.
Type: Article
Language: en
Keywords: Plasma Membrane
Ca2+ Pump 4b
Proapoptotic Tumor Suppressor
Ras-associated Factor 1
RASSF1
ISSN: 0021-9258
Appears in Collections: Molecular Pharmacology Research Group

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