3 years ago

Non-canonical roles of PFKFB3 in regulation of cell cycle through binding to CDK4

Non-canonical roles of PFKFB3 in regulation of cell cycle through binding to CDK4
Wenzhi Jia, Hui Yan, Li Zhao, Jiajin Li, Jianjun Liu, Gang Huang, Hao Yang, Xiaoping Zhao
There is growing interest in studying the molecular mechanisms of crosstalk between cancer metabolism and the cell cycle. 6-phosphate fructose-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is a well-known glycolytic activator that plays an important role in tumorigenesis. We investigated whether PFKFB3 was directly involved in oncogenic signaling networks. Mass Spectrometry showed that PFKFB3 interacts with cyclin-dependent kinase (CDK) 4, which controls the transition from G1 phase to S phase of the cell cycle. Further analysis indicated that lysine 147 was a key site for the binding of PFKBFB3 to CDK4. PFKFB3 binding resulted in the accumulation of CDK4 protein by inhibiting ubiquitin proteasome degradation mediated by the heat shock protein 90-Cdc37–CDK4 complex. The proteasome-dependent degradation of CDK4 was accelerated by disrupting the interaction of PFKFB3 with CDK4 by mutating lysine (147) to alanine. Blocking PFKFB3–CDK4 interaction improved the therapeutic effect of FDA-approved CDK4 inhibitor palbociclib on breast cancer. These findings suggest that PFKFB3 is a hub for coordinating cell cycle and glucose metabolism. Combined targeting of PFKFB3 and CDK4 may be new strategy for breast cancer treatment.

Publisher URL: https://www.nature.com/articles/s41388-017-0072-4

DOI: 10.1038/s41388-017-0072-4

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.