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Syndecan-4 regulates subcellular localization of mTOR Complex2 and Akt activation in a PKCalpha-dependent manner in

Chohreh Partovian1, Rong Ju, Zhen W Zhuang

  • 1Angiogenesis Research Center, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.

Molecular Cell
|October 15, 2008
PubMed

Insights

Syndecan-4 protein targets PKCalpha to cell membranes, enabling mTORC2 complex assembly. This process is crucial for Akt activation, endothelial cell function, and blood pressure regulation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Physiology

Background:

  • Mammalian target of rapamycin (mTOR) signaling is vital for cell growth and survival.
  • mTOR functions through two complexes: mTORC1 and mTORC2.
  • mTORC2 is known to regulate Akt activation, a key signaling pathway.

Purpose of the Study:

  • To investigate the role of syndecan-4 (S4) in regulating mTORC1 and mTORC2 activity in endothelial cells.
  • To elucidate the mechanism by which S4 influences mTORC2 localization and function.
  • To determine the downstream consequences of S4 deficiency on endothelial cell signaling and physiological parameters.

Main Methods:

  • Utilized syndecan-4 (S4) null endothelial cells and S4(-/-) mice.
  • Assessed levels of mTORC1 and mTORC2 components (rictor, mLST8, mSin-1) and PKCalpha in cell lysates and membrane rafts.
  • Investigated the effect of myristoylated-PKCalpha expression and PKCalpha knockdown on mTORC2 localization and Akt phosphorylation.
  • Measured endothelial cell size and arterial blood pressure in S4(-/-) mice.

Main Results:

  • S4 deficiency reduced mTORC2 activity and Akt phosphorylation in endothelial cells.
  • mTORC2 components and PKCalpha were decreased in membrane rafts of S4(-/-) cells.
  • Restoring PKCalpha in S4(-/-) cells rescued mTORC2 localization and Akt activation.
  • PKCalpha knockdown mimicked S4 deletion effects on mTORC2 and Akt.
  • Reduced mTORC2 activity led to decreased phosphorylation of FoxO1/3a and eNOS, smaller endothelial cells, and elevated blood pressure in S4(-/-) mice.

Conclusions:

  • Syndecan-4 (S4) is essential for recruiting PKCalpha to the plasma membrane rafts.
  • PKCalpha recruitment is required for the proper localization of mTORC2 components.
  • This S4-PKCalpha-mTORC2 axis is critical for Akt activation and endothelial cell homeostasis.
  • Dysregulation of this pathway contributes to altered vascular function and hypertension.

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