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p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition

Keelan Z Guiley1,2, Jack W Stevenson2, Kevin Lou2

  • 1Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA.

Science (New York, N.Y.)
|December 14, 2019
PubMed

Insights

Phosphorylated p27 protein activates CDK4, promoting cell proliferation. This activated complex is resistant to the drug palbociclib, which targets inactive CDK4/6, revealing a new mechanism in cancer.

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • Cancer Therapeutics

Background:

  • p27 protein typically inhibits cyclin-dependent kinases (CDKs) to control cell proliferation.
  • The mechanism by which p27 associates with active CDK4 has remained unclear.
  • Understanding CDK regulation is crucial for cancer therapy.

Purpose of the Study:

  • To elucidate the mechanism of CDK4 activation by p27.
  • To investigate the structural and functional consequences of p27 phosphorylation.
  • To determine the sensitivity of the p27-CDK4 complex to CDK4/6 inhibitors.

Main Methods:

  • Protein phosphorylation assays using tyrosine kinases.
  • Structural analysis of protein complexes.
  • Biochemical assays to measure kinase activity.
  • Drug sensitivity testing with palbociclib.

Main Results:

  • Phosphorylated p27 (phosp27) allosterically activates CDK4 in complex with cyclin D1 (CDK4-CycD1).
  • phosp27 binding alters the CDK4 active site, enhancing phosphorylation of substrates like retinoblastoma protein (Rb).
  • The phosp27-CDK4-CycD1 complex is insensitive to palbociclib, while the drug targets monomeric CDK4/6.

Conclusions:

  • Phosphorylated p27 forms an active Rb kinase complex (phosp27-CDK4-CycD1) with unique regulatory properties.
  • This complex represents a novel, drug-resistant form of CDK4/6 activity.
  • Findings suggest new therapeutic strategies targeting resistant CDK4/6 complexes in cancer.

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