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Connective tissue growth factor CCN2 interacts with and activates the tyrosine kinase receptor TrkA

Nadia Abdel Wahab1, Benjamin S Weston, Roger M Mason

  • 1Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 ONN, UK. nadia.wahab@imperial.ac.uk

Journal of the American Society of Nephrology : JASN
|December 17, 2004
PubMed

Insights

Connective tissue growth factor (CTGF) promotes fibrosis by activating intracellular signaling. Researchers found that CTGF uses the TrkA receptor tyrosine kinase to mediate these effects in human mesangial cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Nephrology

Background:

  • Connective tissue growth factor (CTGF) is linked to tissue fibrosis in conditions like diabetic nephropathy.
  • The precise molecular mechanisms underlying CTGF's role in fibrosis remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism of Connective tissue growth factor (CTGF) signaling in human mesangial cells (HMC).
  • To identify the receptor mediating CTGF's intracellular effects.

Main Methods:

  • Human mesangial cells (HMC) were treated with CTGF.
  • Tyrosine phosphorylation was analyzed via Western blot and immunoprecipitation.
  • Receptor-ligand interactions were studied using cross-linking.
  • Inhibitor studies with K252a were performed to assess pathway involvement.

Main Results:

  • CTGF rapidly activated multiple intracellular signaling molecules (ERK1/2, JNK, Akt, CaMK II, PKCα/δ) in HMC.
  • Tyrosine phosphorylation of specific proteins, including the neurotrophin receptor TrkA, was observed.
  • CTGF formed complexes with TrkA and p75(NTR) on the cell surface.
  • CTGF-induced TrkA phosphorylation and downstream signaling were blocked by the Trk inhibitor K252a.

Conclusions:

  • TrkA functions as a tyrosine kinase receptor for Connective tissue growth factor (CTGF).
  • This TrkA-mediated signaling pathway is crucial for CTGF-induced cellular responses, including the induction of TGF-beta-inducible early gene.

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