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APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway

Xiaoban Xin1, Lijun Zhou, Caleb M Reyes

  • 1Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.

American Journal of Physiology. Endocrinology and Metabolism
|October 28, 2010
PubMed

Insights

Adaptor protein APPL1 acts as a scaffold, facilitating adiponectin signaling to activate the p38 MAPK pathway via TAK1 and MKK3. This mechanism is specific to adiponectin stimulation.

Area of Science:

  • Cell biology
  • Molecular signaling
  • Biochemistry

Background:

  • Adiponectin is a key hormone in metabolic regulation.
  • The adaptor protein APPL1 is known to mediate adiponectin's effects.
  • The precise mechanism by which APPL1 influences p38 MAPK signaling remains incompletely understood.

Purpose of the Study:

  • To elucidate the role of APPL1 in adiponectin-stimulated p38 MAPK activation.
  • To identify the specific components of the signaling cascade regulated by APPL1.
  • To determine the selectivity of APPL1's scaffolding function in MAPK activation.

Main Methods:

  • Utilized C(2)C(12) cell lines for overexpression and suppression studies.
  • Employed in vitro affinity binding assays.
  • Performed coimmunoprecipitation experiments.
  • Investigated p38 MAPK phosphorylation in response to adiponectin and TNFα stimulation.

Main Results:

  • APPL1 overexpression enhanced, while suppression reduced, adiponectin-stimulated p38 MAPK activation.
  • APPL1 interacts with both TAK1 and MKK3, key components of the p38 MAPK upstream cascade.
  • APPL1's scaffolding role facilitates the activation of the TAK1-MKK3-p38 MAPK pathway.
  • APPL1's effect on p38 MAPK activation is selective, not affecting TNFα-stimulated signaling.

Conclusions:

  • The TAK1-MKK3 cascade is a critical mediator of adiponectin signaling.
  • APPL1 functions as a specific scaffold protein, crucial for adiponectin-induced activation of the TAK1-MKK3-p38 MAPK pathway.
  • This study reveals a novel mechanism for adiponectin signal transduction in muscle cells.

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