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JNKs function as CDK4-activating kinases by phosphorylating CDK4 and p21

B Colleoni1, S Paternot1, J M Pita1

  • 1WELBIO, Institute of Interdisciplinary Research (IRIBHM) and ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles, Brussels, Belgium.

Oncogene
|April 4, 2017
PubMed

Insights

New research reveals that c-Jun N-terminal kinases (JNKs) directly activate cyclin D-CDK4 complexes, challenging previous models of cell cycle regulation and cancer. This finding highlights JNKs as key players in cell proliferation control.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Cyclin D-CDK4/6 complexes are crucial regulators of cell cycle progression, and their deregulation is implicated in cancer.
  • Previously, cyclin H-CDK7-Mat1 (CAK) was considered the primary CDK-activating kinase, but its constitutive activity posed questions about regulated CDK4 activation.
  • Specific proline at CDK4 (P173) suggested a distinct activation mechanism compared to CDK6 and CDK1/2.

Purpose of the Study:

  • To identify the specific kinases responsible for the activating phosphorylation of CDK4 at T172.
  • To investigate the role of proline-directed kinases, particularly JNKs, in cyclin D-CDK4 activation.
  • To elucidate the interplay between JNKs, CDK4, and p21 in regulating cell proliferation.

Main Methods:

  • Investigated the kinase activity of JNKs, ERK1/2, and CAK on cyclin D-CDK4 complexes.
  • Utilized site-directed mutagenesis to assess the role of p21 phosphorylation sites (S130, T57) in CDK4 activation.
  • Employed JNK inhibitors and chemical genetics in MEFs (mouse embryonic fibroblasts) to confirm JNK2 involvement.

Main Results:

  • JNKs, but not ERK1/2 or CAK, were identified as direct activating kinases for p21-inactivated cyclin D-CDK4.
  • JNKs and ERK1/2 phosphorylated p21 at S130 and T57, though these sites were not essential for JNK-mediated CDK4 phosphorylation.
  • JNK inhibition specifically blocked cyclin D1-CDK4-p21 activation in tumor cells, while cyclin D3-CDK4/p27 activation remained unaffected.

Conclusions:

  • JNKs are key activating kinases for cyclin D1-CDK4 complexes when bound to p21.
  • JNKs can independently phosphorylate both CDK4 and p21, suggesting a dual role in regulating this complex.
  • These findings challenge the established view of CDK activation and highlight JNKs as potential therapeutic targets in specific cancers.

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