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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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PAK4 phosphorylates cyclin-dependent kinase 2 to promote the G1/S transition during adipogenesis

Hwang Chan Yu1, Su Hyeon Park1, Hye Jin Jo2

  • 1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.

Experimental & Molecular Medicine
|September 29, 2025
PubMed

Insights

p21-activated kinase 4 (PAK4) is crucial for adipocyte differentiation, impacting fat mass. This discovery highlights PAK4 as a potential therapeutic target for obesity treatment.

Area of Science:

  • Cell Biology
  • Metabolism
  • Molecular Biology

Background:

  • p21-activated kinase 4 (PAK4) is known for its role in tumor development.
  • Recent studies identified PAK4's involvement in triacylglycerol lipolysis in adipocytes.
  • PAK4's function in adipogenesis was previously unclear.

Purpose of the Study:

  • To investigate the role of PAK4 in adipocyte differentiation.
  • To elucidate the molecular mechanisms by which PAK4 regulates adipogenesis.
  • To assess the therapeutic potential of targeting PAK4 for obesity treatment.

Main Methods:

  • Studied PAK4 protein levels during adipogenic stimulation.
  • Utilized PAK4 knockdown in 3T3-L1 preadipocytes and human stromal vascular cells.
  • Employed pharmacological inhibition of PAK4 in 3T3-L1 cells.
  • Analyzed adipocyte marker gene expression and lipid accumulation.
  • Investigated PAK4's phosphorylation of cyclin-dependent kinase 2 (CDK2).
  • Examined fat mass and adipocyte size in preadipocyte-specific Pak4-knockout mice.

Main Results:

  • PAK4 protein levels increased following adipogenic stimulation.
  • PAK4 knockdown or inhibition impaired adipogenesis, reducing adipocyte marker gene expression and lipid accumulation.
  • PAK4 was found to phosphorylate CDK2 at serine 106, a key step for CCAAT/enhancer-binding protein β expression during mitotic clonal expansion.
  • Preadipocyte-specific Pak4-knockout mice showed reduced fat mass and smaller adipocytes.

Conclusions:

  • PAK4 plays a critical role in regulating adipocyte differentiation.
  • PAK4's function in promoting adipogenesis, alongside its inhibitory role in lipolysis, makes it a significant target for obesity therapeutics.

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