Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β

Fahd Al-Mulla, Milad S. Bitar, May Al-Maghrebi, Abdulla I. Behbehani, Waleed Al-Ali, Oliver Rath, Brendan Doyle, Kit Yee Tan, Andrew Pitt, Walter Kolch

Research output: Contribution to journalArticle

Abstract

Raf kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-RAF kinase and nuclear factor ?B signaling that represses tumor invasion and metastasis. Glycogen synthase kinase-3ß (GSK3ß) suppresses tumor progression by downregulating multiple oncogenic pathways including Wnt signaling and cyclin D1 activation. Here, we show that RKIP binds GSK3 proteins and maintains GSK3ß protein levels and its active form. Depletion of RKIP augments oxidative stress-mediated activation of the p38 mitogen activated protein kinase, which, in turn, inactivates GSK3ß by phosphorylating it at the inhibitory T390 residue. This pathway de-represses GSK3ß inhibition of oncogenic substrates causing stabilization of cyclin D, which induces cell-cycle progression and ß-catenin, SNAIL, and SLUG, which promote epithelial to mesenchymal transition. RKIP levels in human colorectal cancer positively correlate with GSK3ß expression. These findings reveal the RKIP/GSK3 axis as both a potential therapeutic target and a prognosis-based predictor of cancer progression.
LanguageEnglish
Pages1334-1343
Number of pages10
JournalCancer Research
Volume71
Issue number4
Early online date8 Feb 2011
DOIs
Publication statusPublished - 15 Feb 2011

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Phosphatidylethanolamine Binding Protein
raf Kinases
Glycogen Synthase Kinases
Protein Kinases
Proteins
Cyclin D
Catenins
Neoplasms
Wnt Signaling Pathway
Epithelial-Mesenchymal Transition
Cyclin D1
p38 Mitogen-Activated Protein Kinases
Colorectal Neoplasms
Cell Cycle
Oxidative Stress
Phosphotransferases
Down-Regulation
Neoplasm Metastasis

Keywords

  • animals
  • carcinoma
  • cultured cells
  • colorectal neoplasms
  • disease progression
  • enzyme stability
  • glycogen synthase kinase 3
  • humans
  • mice
  • knockout mice
  • oxidative stress
  • phosphatidylethanolamine binding protein
  • phosphorylation
  • protein binding
  • signal transduction
  • up-regulation

Cite this

Al-Mulla, F., Bitar, M. S., Al-Maghrebi, M., Behbehani, A. I., Al-Ali, W., Rath, O., ... Kolch, W. (2011). Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β. Cancer Research, 71(4), 1334-1343. https://doi.org/10.1158/0008-5472.CAN-10-3102
Al-Mulla, Fahd ; Bitar, Milad S. ; Al-Maghrebi, May ; Behbehani, Abdulla I. ; Al-Ali, Waleed ; Rath, Oliver ; Doyle, Brendan ; Tan, Kit Yee ; Pitt, Andrew ; Kolch, Walter. / Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β. In: Cancer Research. 2011 ; Vol. 71, No. 4. pp. 1334-1343.
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Al-Mulla, F, Bitar, MS, Al-Maghrebi, M, Behbehani, AI, Al-Ali, W, Rath, O, Doyle, B, Tan, KY, Pitt, A & Kolch, W 2011, 'Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β' Cancer Research, vol. 71, no. 4, pp. 1334-1343. https://doi.org/10.1158/0008-5472.CAN-10-3102

Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β. / Al-Mulla, Fahd; Bitar, Milad S.; Al-Maghrebi, May; Behbehani, Abdulla I.; Al-Ali, Waleed; Rath, Oliver; Doyle, Brendan; Tan, Kit Yee; Pitt, Andrew; Kolch, Walter.

In: Cancer Research, Vol. 71, No. 4, 15.02.2011, p. 1334-1343.

Research output: Contribution to journalArticle

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AU - Al-Maghrebi, May

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AU - Al-Ali, Waleed

AU - Rath, Oliver

AU - Doyle, Brendan

AU - Tan, Kit Yee

AU - Pitt, Andrew

AU - Kolch, Walter

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KW - knockout mice

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KW - phosphorylation

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KW - signal transduction

KW - up-regulation

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Al-Mulla F, Bitar MS, Al-Maghrebi M, Behbehani AI, Al-Ali W, Rath O et al. Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β. Cancer Research. 2011 Feb 15;71(4):1334-1343. https://doi.org/10.1158/0008-5472.CAN-10-3102