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Published ahead of print on December 15, 2004
J Am Soc Nephrol 16: 340-351, 2005
© 2005 American Society of Nephrology
doi: 10.1681/ASN.2003100905
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Cell Biology

Connective Tissue Growth Factor CCN2 Interacts with and Activates the Tyrosine Kinase Receptor TrkA

Nadia Abdel Wahab, Benjamin S. Weston and Roger M. Mason

Cell and Molecular Biology Section, Division of Biomedical Sciences, Faculty of Medicine, Imperial College London, South Kensington, London, United Kingdom

Address correspondence to: Dr. Nadia Wahab, Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 ONN, UK. Phone: +44-20-838-32718; Fax: +44-20-838-32062; E-Mail: nadia.wahab{at}imperial.ac.uk

Connective tissue growth factor (CTGF) is implicated as a factor promoting tissue fibrosis in several disorders, including diabetic nephropathy. However, the molecular mechanism(s) by which it functions is not known. CTGF rapidly activates several intracellular signaling molecules in human mesangial cells (HMC), including extracellular signal-related kinase 1/2, Jun NH2-terminal kinase, protein kinase B, CaMK II, protein kinase C{alpha}, and protein kinase C{delta}, suggesting that it functions via a signaling receptor. Treating HMC with CTGF stimulated tyrosine phosphorylation of proteins 75 to 80 and 140 to 180 kD within 10 min, and Western blot analysis of anti-phosphotyrosine immunoprecipitates identified the neurotrophin receptor TrkA (molecular weight approximately 140 kD). Cross-linking rCTGF to cell surface proteins with 3,3'-dithiobis(sulfosuccinimidylpropionate) revealed that complexes formed with TrkA and with the general neurotrophin co-receptor p75NTR. rCTGF stimulated phosphorylation of TrkA (tyr 490, 674/675). K252a, a known selective inhibitor of Trk, blocked this phosphorylation, CTGF-induced activation of signaling proteins, and CTGF-dependent induction of the transcription factor TGF-{beta}-inducible early gene in HMC. It is concluded that TrkA serves as a tyrosine kinase receptor for CTGF.




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