Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The small GTP-binding proteins Rac1 and Rac2 are critically important in regulating multiple signal transduction pathways in eukaryotic cells. Here we report the isolation of a novel third Rac family member, Rac3. Rac3 differs from Rac1/2 at its carboxyl-terminal end, a domain associated with subcellular localization and binding to specific cellular regulators. RAC3 mRNA expression patterns differ from those of RAC2, which is hematopoietic specific and also from those of RAC1. The RAC3 gene was mapped to chromosome 17q23-25, a region frequently deleted in breast cancer. Rac3 protein levels are not affected by organization of the actin cytoskeleton but remarkably, are serum-inducible. Rac3 is an active GTPase, and this activity is regulated by Bcr. When constitutively activated, Rac3 is able to stimulate efficiently the c-Jun amino-terminal kinase signaling pathway. These findings support a role for Rac3 in intracellular signaling.
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PMID:Characterization of RAC3, a novel member of the Rho family. 925 44

Rac1, a Rho family GTPase, is a mediator of diverse cellular functions including membrane ruffling, cell cycle progression, and transformation. Rac3, a close relative of Rac1, is less well characterized. Posttranslational addition of geranylgeranyl isoprenoid lipids to Rac proteins is required for biological activity. Inhibitors of geranylgeranyl transferase I (GGTIs) are currently under investigation as a possible anticancer therapy, although the targets of GGTIs have not been determined. We created COOH-terminal mutants of Rac1 and Rac3 that are farnesylated and used them to characterize Rac1 and Rac3 as physiological targets of GGTIs. We show that, like Rac1, activated Rac3 causes transformation and leads to membrane ruffling. Farnesylated versions of Rac1 and Rac3 retain the ability to signal to the transcription factor c-Jun and cause membrane ruffling and transformation, indicating that switching isoprenoid modification does not alter function. Finally, treatment with GGTIs led to the inhibition of membrane-ruffling and transforming activities of both activated and wild-type Rac1 and Rac3. However, the farnesylated versions of both activated and wild-type Rac1 and Rac3 were resistant to the inhibitory effects of GGTIs. These results illustrate that Rac1 and Rac3 are potential physiological targets for these novel drugs.
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PMID:Rac1 and Rac3 are targets for geranylgeranyltransferase I inhibitor-mediated inhibition of signaling, transformation, and membrane ruffling. 1463 27