Preparing your results

Our searching services are busy right now. Your search will reload in five seconds.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Regulation of Raf-1 by direct feedback phosphorylation.

Molecular cell | Jan 21, 2005

http://www.ncbi.nlm.nih.gov/pubmed/15664191

The Raf-1 kinase is an important signaling molecule, functioning in the Ras pathway to transmit mitogenic, differentiative, and oncogenic signals to the downstream kinases MEK and ERK. Because of its integral role in cell signaling, Raf-1 activity must be precisely controlled. Previous studies have shown that phosphorylation is required for Raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of Raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli. The hyperphosphorylated/desensitized Raf-1 is subsequently dephosphorylated and returned to a signaling-competent state through interactions with the protein phosphatase PP2A and the prolyl isomerase Pin1. These findings elucidate a critical Raf-1 regulatory mechanism that contributes to the sensitive, temporal modulation of Ras signaling.

Pubmed ID: 15664191 RIS Download

Mesh terms: Animals | Cell Line | Down-Regulation | Enzyme Activation | Extracellular Signal-Regulated MAP Kinases | Feedback, Physiological | Isoenzymes | Mice | Mutagenesis, Site-Directed | Peptides | Peptidylprolyl Isomerase | Phosphoprotein Phosphatases | Phosphorylation | Platelet-Derived Growth Factor | Proto-Oncogene Proteins c-raf | Receptors, Platelet-Derived Growth Factor | Signal Transduction | Xenopus laevis | ras Proteins

Research resources used in this publication

None found

Research tools detected in this publication

None found

Data used in this publication

None found

Associated grants

  • Agency: NIGMS NIH HHS, Id: R01GM58556

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.