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Regulation of raf-1 by direct feedback phosphorylation

  1. Author:
    Dougherty, M. K.
    Muller, J.
    Ritt, D. A.
    Zhou, M.
    Zhou, X. Z.
    Copeland, T. D.
    Conrads, T. P.
    Veenstra, T. D.
    Lu, K. P.
    Morrison, D. K.

  2. Author Address

    Natl Canc Inst, Lab Prot Dynam & Signaling, Ft Detrick, MD 21702 USA. Sci Applicat Int Corp, Lab Proteom & Analyt Technol, Ft Detrick, MD 21702 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA Morrison, DK, Natl Canc Inst, Lab Prot Dynam & Signaling, Ft Detrick, MD 21702 USA
    1. Year: 2005
    2. Date: JAN 21
  2. Journal: Molecular Cell
    1. 17
    2. 2
    3. Pages: 215-224
  4. Type of Article: Article
  1. Abstract:

    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

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External Sources

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  2. DOI: 10.1016/j.molcel.2004.11.055
  3. View record in Web of Science®
  4. WOS: 000226596100009

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