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Akt acts as a switch for GPCR transactivation of the TGF-β receptor type 1

Raafat Mohamed1, Aravindra Shajimoon1,2, Rizwana Afroz1

  • 1School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Australia.

The FEBS Journal
|November 26, 2021
PubMed

Insights

Protein kinase B (Akt) activation enables G protein-coupled receptors (GPCRs) to phosphorylate Smad2C via TGF-β receptors. Akt agonist SC79 facilitates this process by moving TGF-β receptors to the cell surface.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Receptor biology

Background:

  • Transforming growth factor-beta (TGF-β) signaling is initiated by ligand binding to TGF-β receptors (TGFBR), leading to Smad2 phosphorylation and cellular responses.
  • G protein-coupled receptors (GPCRs) can transactivate TGFBR1, but this mechanism is not universally observed, as demonstrated in keratinocytes with thrombin.
  • TGF-β receptors (TGFBRs) are primarily cytosolic and can translocate to the cell surface upon protein kinase B (Akt) phosphorylation, enhancing TGF-β responsiveness.

Purpose of the Study:

  • To investigate the role of Akt in GPCR-mediated transactivation of TGFBR1.
  • To elucidate the mechanism by which Akt influences GPCR transactivation of TGFBR1.
  • To determine if Akt activation can overcome the lack of GPCR transactivation observed in certain cell types.

Main Methods:

  • Utilized human vascular smooth muscle cells and keratinocytes.
  • Investigated the phosphorylation of Smad2 carboxyl-terminal (phospho-Smad2C) in response to GPCR agonists (angiotensin II, thrombin).
  • Employed the Akt agonist SC79 to modulate Akt activity and observed the translocation of TGFBRs to the cell surface.

Main Results:

  • Angiotensin II and thrombin did not induce phospho-Smad2C in human vascular smooth muscle cells and keratinocytes, respectively, without Akt modulation.
  • Activation of Akt using SC79 led to angiotensin II and thrombin-induced phospho-Smad2C via Akt/AS160-dependent pathways.
  • SC79 treatment rapidly translocated TGFBRs to the cell surface, enhancing cellular response to GPCR agonists.

Conclusions:

  • Akt plays a crucial role in GPCR transactivation of TGFBR1.
  • Akt-mediated translocation of TGFBRs to the cell surface is a key mechanism for enhancing GPCR-induced signaling.
  • These findings provide novel insights into the interplay between Akt, GPCRs, and TGF-β signaling pathways.
Keywords:
SC79Smadangiotensin IIthrombin

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