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

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Connective Tissue Growth Factor CCN2 Interacts with and Activates the Tyrosine Kinase Receptor Trka 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 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 , and protein kinase C , 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(sulfosuccin imidylpropionate) 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 phosphoryla- tion, CTGF-induced activation of signaling proteins, and CTGF-dependent induction of the transcription factor TGF-␤– inducible early gene in HMC. It is concluded that TrkA serves as a tyrosine kinase receptor for CTGF. J Am Soc Nephrol 16: 340–351, 2005. doi: 10.1681/ASN.2003100905 onnective tissue growth factor (CTGF; CCN2) is a Recently, we proposed that CTGF directly enhances the TGF- 38-kD secreted protein with multiple domains, en- ␤/Smad signaling pathway. The mechanism underlying this C coded by an immediate-early gene, and is a member seems to be via the rapid induction of the transcription factor of the CCN protein family (1). An increasing number of TGF-␤–inducible early gene (TIEG) (11). TIEG has been shown to studies in the past few years indicate that CTGF is strongly bind to the promoter of the Smad7 gene and represses its tran- implicated in the pathogenesis of a variety of fibrotic disor- scription (12). Because Smad7 is a potent inhibitory Smad, it seems ders, including diabetic nephropathy (2). Functionally, the that CTGF simply blocks the negative feedback loop of the TGF-␤ growth factor has been shown to regulate many aspects of signaling pathway, allowing its continued activation. The rapid cell behavior, including cell adhesion, migration, growth, activation of several intracellular signaling pathways by CTGF, chemotaxis, and the synthesis and accumulation of matrix together with its ability to induce the expression of several genes proteins (3). However, the molecular mechanism(s) by which in mesangial cells, including the early gene TIEG, suggested that it functions is not clear. The presence of multiple domains in a specific signaling receptor must exist. Previous cross-linking CTGF suggests a role for the growth factor as an integrator of studies revealed CTGF-receptor complexes with an apparent mo- several other signaling molecules such as growth factors, lecular weight of 280 kD, present in chondrocytes, osteoblasts, and integrins, and extracellular matrix proteins. CTGF has been endothelial cells (13). CTGF was also found to bind to LDL recep- reported to bind directly bone morphogenic protein–4 and tor–related protein. However, this may facilitate clearance rather ␤ TGF- through its von Willebrand type C domain, leading to than signal transduction (14). inhibition of bone morphogenic protein and enhancement of In the present report, we provide for the first time evidence ␤ TGF- signaling (4). CTGF also has been shown to bind to that CTGF interacts with TrkA and p75NTR, a dual-receptor integrins (5–10), and this interaction may mediate some of system that is known to transduce neurotrophin signals. There the cellular phenomena mentioned above. are three Trk receptor tyrosine kinase genes (TrkA, TrkB, and TrkC) and a single gene encoding the neurotrophin receptor, p75NTR. On ligand binding, Trk dimerize and autophosphory- Received October 31, 2003. Accepted October 25, 2004. late, leading to the activation of several small G proteins, in- Published online ahead of print. Publication date available at www.jasn.org. cluding Ras, Rap-1, and the Cdc 42-Rac-Rho family, as well as Address correspondence to: Dr. Nadia Wahab, Renal Section, Division of Med- of pathways regulated by mitogen activated protein kinase icine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, (MAPK), phosphatidylinositol 3-kinase, and phospholipase C-␥ ϩ ϩ W12 ONN, UK. Phone: 44-20-838-32718; Fax: 44-20-838-32062; E-Mail: (15). On activation, Trk also promote a rapid increase in cyto- [email protected] plasmic calcium level. This seems to arise from both release of The current affiliation for N.A.W. and R.M.M. is Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital, London, United intracellular stores and uptake of extracellular calcium (16,17). Kingdom. Moreover, activated Trk interact, directly or indirectly, with Copyright © 2005 by the American Society of Nephrology ISSN: 1046-6673/1602-0340 J Am Soc Nephrol 16: 340–351, 2005 CTGF Activates the TrkA Receptor 341 many cytoplasmic adaptor proteins, leading to a variety of nant CTGF (CTGF/V5 fusion protein) was expressed in transformed biologic responses, including, cell proliferation and survival; HMC and purified from the medium using Talon metal affinity resin, axonal and dendritic growth and remodeling; assembly and as reported previously (2). Alternatively, r-CTGF (nonfusion protein) remodeling of cytoskeleton; membrane trafficking and fusion; was expressed in the baculovirus system and was a gift from FibroGen Inc. (South San Francisco, CA). Rabbit anti-CTGF (pAb2) and chicken and synapse formation, function, and plasticity (18). NTR anti-CTGF (pIgY3) were also supplied by FibroGen Inc. Phosphothioate The pan-neurotrophin receptor p75 is a member of a antisense and control oligonucleotides directed to TrkA (GTGAAGAT- superfamily that includes the TNF, B cell antigen CD40, and Fas GAAGCTGGT; ACTACTACACTAGACTAC) and p75NTR (TTCTGCT- NTR receptors (19). p75 signals via pathways involved with ac- TGTCCTG; GCTCTATGACTCCCAG) were designed and manufac- tivation of sphingomyelinase and ceramide production (20), tured by Biognostik GmbH (Go¨ttingen, Germany), who own the ␬ NF- B (21), and Jun NH2-terminal kinase (JNK) (22). Although intellectual property rights to the sequences. both receptors mediate the biologic effects of neurotrophins, it seems that Trk play the central role in signaling. However, the contribution of p75NTR is not fully understood. It has been Cross-Linking and Membrane Preparation proposed that p75NTR can act as a co-receptor with Trk to create Cell layers were washed twice with cold binding buffer (PBS and 0.5% glucose) and incubated with CTGF in binding buffer for2hat4°C. high-affinity receptors for different neurotrophins (23) either by After incubation, the cell layers were washed five times with cold presenting the ligand to the Trk receptor, or by altering the binding buffer and incubated with 1 mM 3,3Ј-dithiobis(sulfosuccinimi- conformation of the Trk receptors through allosteric interaction dylpropionate) (DTSSP) or disuccinimidyl suberate (Pierce Biotechnol- (24). It can also function on its own (25). Yet another interesting ogy, Tattenhall, Cheshire, UK) in PBS for 30 min at room temperature. NTR finding is that p75 can function as a receptor for the imma- The reaction was quenched for 15 min at room temperature by the ture unprocessed forms of neurotrophins, whereas Trk func- addition of 50 mM Tris buffer (pH 7.5). Cell layers were washed with tions as a receptor for the mature forms (26). Cross-talk be- wash buffer (10 mM Tris buffer [pH 7.5], 5 mM MgCl, and 150 mM tween the Trk and other membrane receptors, such as G NaCl), scraped in homogenizing buffer (10 mM Tris buffer [pH 7.5], 250 ϫ protein–coupled receptor, vannilloid receptor, and c-Ret, have mM sucrose, 1 mM EDTA, 5 mM MgCl, 150 mM NaCl, and 1 protease inhibitor cocktail; Roche Applied Science, Mannheim, Germany), also been reported (18). passed through a 25-G needle, and homogenized on ice with 30 to 40 Ligand engagement stimulates the endocytosis of the ligand– cycles in a Dounce homogenizer. The homogenate was centrifuged for Trk complex into vesicles via a clathrin-dependent mechanism 10 min at 2500 ϫ g at 4°C. The resulting supernatant was centrifuged (27). The receptors remain catalytically active within the sorting for 90 min at 45,000 ϫ g at 4°C. The membrane-enriched pellet was vesicles, which are called “signaling endosomes” (28). Inhibit- solubilized for 1 h in solubilizing buffer (10 mM Tris buffer [pH 7.5], 5 ing endocytosis inhibits extracellular signal–related kinase mM MgCl, 150 mM NaCl, 1% Triton-X100, and 1ϫ protease inhibitor (ERK) 1/2 activation in response to neurotrophin stimulation cocktail). Soluble membrane proteins were collected after further cen- (29). trifugation for1hat45,000 ϫ g at 4°C. When rCTGF/V5 fusion protein As Trk receptors have been found to bind a large number of was used, CTGF cross-linked proteins were either immunoprecipitated with rabbit anti-CTGF antibody or captured on a Pull-Down PolyHis adaptor proteins and multiple intracellular signaling pathways column (Pierce). When rCTGF was used, CTGF cross-linked proteins are activated by them, as well as modulated by p75NTR, this were captured on a goat anti–CTGF-C terminal domain–sepharose may explain the multifunctional properties of CTGF. The re- immunoaffinity column, using an IgG-sepharose column as a control sults presented in this study show that Trk tyrosine kinase (FibroGen Inc.). After extensive washing of the columns with solubi- activity is required for the CTGF-dependent induction of the lizing buffer, bound proteins were solubilized in reducing SDS-PAGE transcription factor TIEG.
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