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P21-activated protein kinase (PAK2)-mediated c-Jun phosphorylation at 5 threonine sites promotes cell transformation

Tingting Li1, Jishuai Zhang, Feng Zhu

  • 1The Hormel Institute, University of Minnesota, 801 16th Avenue North East, Austin, MN 55912, USA.

Carcinogenesis
|December 24, 2010
PubMed

Insights

Epidermal growth factor (EGF) triggers P21-activated kinase 2 (PAK2) to phosphorylate the c-Jun oncoprotein. This PAK2/c-Jun signaling pathway is crucial for EGF-induced cell proliferation and malignant transformation.

Area of Science:

  • Molecular biology
  • Cell signaling
  • Oncology

Background:

  • The activator protein-1 (AP-1) transcription factor complex, including the oncoprotein c-Jun, regulates genes involved in cell growth, differentiation, and apoptosis.
  • AP-1 activity is implicated in promoting tumorigenesis and malignant transformation by activating tumor-related genes.

Purpose of the Study:

  • To investigate the role of P21-activated kinase 2 (PAK2) in epidermal growth factor (EGF)-induced cell proliferation and transformation.
  • To elucidate the mechanism by which PAK2 influences c-Jun activity and its downstream effects.

Main Methods:

  • In vitro and ex vivo binding and phosphorylation assays to determine PAK2's interaction with c-Jun.
  • Site-directed mutagenesis of c-Jun phosphorylation sites.
  • Gene knockdown experiments (PAK2) in JB6 Cl41 and SK-MEL-5 cell lines.
  • Assessment of cell transformation, proliferation, colony formation, and AP-1 activity.

Main Results:

  • PAK2 directly binds and phosphorylates c-Jun at five specific threonine sites (Thr2, Thr8, Thr89, Thr93, Thr286).
  • Knockdown of PAK2 reduced EGF-induced anchorage-independent cell transformation, proliferation, and AP-1 activity in JB6 Cl41 cells.
  • Mutation of the identified PAK2 phosphorylation sites on c-Jun diminished the transforming ability of JB6 cells.
  • PAK2 knockdown also decreased colony formation, proliferation, and AP-1 activity in SK-MEL-5 melanoma cells.

Conclusions:

  • PAK2 plays a significant role in EGF-induced cell proliferation and transformation.
  • The PAK2/c-Jun signaling axis is a key mediator of these cellular processes.
  • Targeting PAK2 may offer therapeutic strategies for inhibiting EGF-driven tumorigenesis.

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