FEBS Letters
Volume 582, Issue 2 , Pages 255-261, 23 January 2008

Multiple PPPS/TP motifs act in a combinatorial fashion to transduce Wnt signaling through LRP6

Edited by Richard Marais

  • Joshua Wolf

      Affiliations

    • Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 211, Bethesda, MD 20892, USA
    • ,
  • Todd R. Palmby

      Affiliations

    • Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 211, Bethesda, MD 20892, USA
    • ,
  • Julie Gavard

      Affiliations

    • Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 211, Bethesda, MD 20892, USA
    • ,
  • Bart O. Williams

      Affiliations

    • Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, MI 49503-2518, USA
    • ,
  • J. Silvio Gutkind

      Affiliations

    • Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 211, Bethesda, MD 20892, USA
    • Corresponding Author InformationCorresponding author. Fax: +1 301 402 0823.

Received 8 October 2007; received in revised form 5 December 2007; accepted 6 December 2007. published online 14 December 2007.

Abstract 

Binding of Wnt to Frizzled, and either of two members of the low-density-lipoprotein receptor-related protein family, LRP5/6, leads to β-catenin activation by a poorly understood mechanism. LRP5/6 exhibit five highly conserved PPPS/TP motifs in their intracellular region, among which the first PPPS/TP site is rapidly phosphorylated upon Wnt stimulation. By the use of full-length LRP6 mutants harboring multiple mutations involving the five PPPS/TP motifs, we found that this first PPPS/TP phosphoacceptor site is alone not sufficient or strictly necessary for β-catenin activation. Instead, we show that each LRP6 PPPS/TP motif contributes in a combinatorial fashion to activate the canonical Wnt-β-catenin pathway.

Keywords: Wnt, LRP6, β-Catenin, Nuclear signaling, Cancer

 

PII: S0014-5793(07)01272-0

doi:10.1016/j.febslet.2007.12.013

FEBS Letters
Volume 582, Issue 2 , Pages 255-261, 23 January 2008

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