Tuberous sclerosis tumor suppressor complex-like complexes act as GTPase-activating proteins for Ral GTPases

Ryutaro Shirakawa, Shuya Fukai, Mitsunori Kawato, Tomohito Higashi, Hirokazu Kondo, Tomoyuki Ikeda, Ei Nakayama, Katsuya Okawa, Osamu Nureki, Takeshi Kimura, Toru Kita, Hisanori Horiuchi

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)21580-21588
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number32
DOIs
Publication statusPublished - 2009 Aug 7
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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