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Increased cell growth due to a new lipase-GEF (Phospholipase D2) fastly acting on Ras.
Henkels, Karen M; Mahankali, Madhu; Gomez-Cambronero, Julian.
Afiliação
  • Henkels KM; Wright State University School of Medicine, Department of Biochemistry and Molecular Biology, OH 45435, USA.
Cell Signal ; 25(1): 198-205, 2013 Jan.
Article em En | MEDLINE | ID: mdl-22960035
We report the novel finding that Phospholipase D2 (PLD2), through its PX and PH domains, binds specifically to Ras and catalyzes the GDP/GTP exchange (i.e., is a GEF), with potency comparable to Ras-GRF-1, a known Ras-GEF. Cells overexpressing PLD2-GEF inactive mutants (F129Y and R172C/L173A) fail to stimulate cell proliferation compared to the wild type-expressing cells. The GEF effect on Ras follows a faster kinetics than other GTPase substrates (such as Rac2 or Rac1) and is a better substrate, too. The GEF action is due to PLD2 (protein) itself, independent of the lipase product PA. PA can still have a fine-tuning regulatory effect on Ras-GTP depending upon its cellular concentration. Rapidly growing human breast cancer cells MDA-MB 231 (but not the slow growing MCF7 counterpart) have high levels of endogenous PLD2-GEF which correlates with high Ras activation. The PLD2-"GEF" activity is even higher than the classical "lipase" activity and is abrogated with GEF single point mutants, particularly F129Y, and concomitantly with a slow rate of cell growth. This can be crucial to cancer biology in that not only Ras mutations explain abnormal growth, but the existence of a new GEF for Ras: a GEF molecule that happens to be a phospholipase.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fosfolipase D / Proteínas ras Idioma: En Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fosfolipase D / Proteínas ras Idioma: En Ano de publicação: 2013 Tipo de documento: Article