Tuberous Sclerosis Tumor Suppressor Complex-like Complexes Act as GTPase-activating Proteins for Ral GTPases*

AUTOR(ES)

Shirakawa, Ryutaro

FONTE

American Society for Biochemistry and Molecular Biology

RESUMO

The small GTPases RalA and RalB are multifunctional proteins regulating a variety of cellular processes. Like other GTPases, the activity of Ral is regulated by the opposing effects of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Although several RalGEFs have been identified and characterized, the molecular identity of RalGAP remains unknown. Here, we report the first molecular identification of RalGAPs, which we have named RalGAP1 and RalGAP2. They are large heterodimeric complexes, each consisting of a catalytic α1 or α2 subunit and a common β subunit. These RalGAP complexes share structural and catalytic similarities with the tuberous sclerosis tumor suppressor complex, which acts as a GAP for Rheb. In vitro GTPase assays revealed that recombinant RalGAP1 accelerates the GTP hydrolysis rate of RalA by 280,000-fold. Heterodimerization was required for this GAP activity. In PC12 cells, knockdown of the β subunit led to sustained Ral activation upon epidermal growth factor stimulation, indicating that the RalGAPs identified here are critical for efficient termination of Ral activation induced by extracellular stimuli. Our identification of RalGAPs will enable further understanding of Ral signaling in many biological and pathological processes.

Documentos Relacionados

• GTPase-Activating Proteins for Cdc42
• GGAPs, a New Family of Bifunctional GTP-Binding and GTPase-Activating Proteins
• Plasma membrane-targeted ras GTPase-activating protein is a potent suppressor of p21ras function.
• Rapid GTP binding and hydrolysis by Gq promoted by receptor and GTPase-activating proteins
• Role of β-Dystrobrevin in Nonmuscle Dystrophin-Associated Protein Complex-Like Complexes in Kidney and Liver