An essential role of Pak1 phosphorylation of SHARP in Notch signaling

Ratna K. Vadlamudi, Bramanandam Manavathi, Rajesh R. Singh, Diep Nguyen, Feng Li, Rakesh Kumar

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

The p21-activated kinases (Paks), an evolutionarily conserved family of serine/threonine kinases, play an important role in cytoskeletal reorganization in mammalian cells. The Notch signaling pathway plays an important role in the determination of cell fate/differentiation in a number of organs. Notch signaling is a complex process, and the mechanism by which Notch regulates multiple cellular processes is intriguing. The expression of both Notch and Pak1 has been shown to be deregulated in several human cancers. Using yeast two-hybrid screening, we identified SHARP, one of the Notch signaling components, as a Pak1-interacting protein. We found that SHARP is a physiologic interacting substrate of Pak1, and that this interaction enhances SHARP-mediated repression of Notch target genes. Pak1 phosphorylation sites in SHARP were mapped to Ser3486 and Thr3568 within the SHARP repression domain. Mutation of Pak1 phosphorylation sites in SHARP, inhibition of Pak1 functions by a Pak1-autoinhibitory fragment (amino acids 83-149), or expression of Pak1-specific siRNA interfered with SHARP-mediated repression of Notch target reporter gene activation. These results demonstrate that Pak1-SHARP interaction plays an essential role in enhancing the corepressor functions of SHARP, thereby modulating Notch signaling in human cancer cells.

Original languageEnglish (US)
Pages (from-to)4591-4596
Number of pages6
JournalOncogene
Volume24
Issue number28
DOIs
StatePublished - Jun 30 2005
Externally publishedYes

Keywords

  • Notch
  • Pak1 signaling
  • Repression
  • SHARP

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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  • Cite this

    Vadlamudi, R. K., Manavathi, B., Singh, R. R., Nguyen, D., Li, F., & Kumar, R. (2005). An essential role of Pak1 phosphorylation of SHARP in Notch signaling. Oncogene, 24(28), 4591-4596. https://doi.org/10.1038/sj.onc.1208672