TGFb acts through PDGFRb to activate mTORC1 via the Akt/PRAS40 axis and causes glomerular mesangial cell hypertrophy and matrix protein expression

Soumya Maity, Falguni Das, Balakuntalam S. Kasinath, Nandini Ghosh-Choudhury, Goutam Ghosh Choudhury

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Interaction of transforming growth factor-b (TGFb)-induced canonical signaling with the noncanonical kinase cascades regulates glomerular hypertrophy and matrix protein deposition, which are early features of glomerulosclerosis. However, the specific target downstream of the TGFb receptor involved in the noncanonical signaling is unknown. Here, we show that TGFb increased the catalytic loop phosphorylation of platelet-derived growth factor receptor b (PDGFRb), a receptor tyrosine kinase expressed abundantly in glomerular mesangial cells. TGFb increased phosphorylation of the PI 3-kinase-interacting Tyr-751 residue of PDGFRb, thus activating Akt. Inhibition of PDGFRb using a pharmacological inhibitor and siRNAs blocked TGFb-stimulated phosphorylation of proline-rich Akt substrate of 40 kDa (PRAS40), an intrinsic inhibitory component of mTORC1, and prevented activation of mTORC1 in the absence of any effect on Smad 2/3 phosphorylation. Expression of constitutively active myristoylated Akt reversed the siPDGFRb-mediated inhibition of mTORC1 activity; however, co-expression of the phospho-deficient mutant of PRAS40 inhibited the effect of myristoylated Akt, suggesting a definitive role of PRAS40 phosphorylation in mTORC1 activation downstream of PDGFRb in mesangial cells. Additionally, we demonstrate that PDGFRb-initiated phosphorylation of PRAS40 is required for TGFb-induced mesangial cell hypertrophy and fibronectin and collagen I (a2) production. Increased activating phosphorylation of PDGFRb is also associated with enhanced TGFb expression and mTORC1 activation in the kidney cortex and glomeruli of diabetic mice and rats, respectively. Thus, pursuing TGFb noncanonical signaling, we identified how TGFb receptor I achieves mTORC1 activation through PDGFRb-mediated Akt/PRAS40 phosphorylation to spur mesangial cell hypertrophy and matrix protein accumulation. These findings provide support for targeting PDGFRb in TGFb-driven renal fibrosis.

Original languageEnglish (US)
Pages (from-to)14262-14278
Number of pages17
JournalJournal of Biological Chemistry
Volume295
Issue number42
DOIs
StatePublished - Oct 16 2020
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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