Gas6 Induces Mesangial Cell Proliferation via Latent Transcription Factor STAT3

Mesangial cell proliferation is essential for the pathogenesis and progression of glomerular disease. Previously, we showed that Gas6 plays a pivotal role in mesangial cell proliferation in vitro and in vivo. In the present study, we identified downstream targets of Gas6 signaling to examine the role in mesangial cell proliferation in vitro and in vivo. We found that Gas6 tyrosine phosphorylates STAT3 (signal transducers and activators of transcription) with concomitant translocation to the nucleus and induces STAT3-dependent transcriptional activation in cultured mesangial cells. Expressing dominant negative STAT3 inhibited Gas6-mediated transcriptional activation of STAT3 and abolished Gas6-induced mesangial cell proliferation. In a model of mesangial proliferative glomerulonephritis, STAT3 is phosphorylated in mesangial cells, and its phosphorylation peaks at day 8 after the injection of anti-Thy1.1 antibody. Inhibition of Gas6 by warfarin and the extracellular domain of its receptor, Axl, abolished phosphorylation of STAT3 in vivo. Thus, our in vitro and in vivo findings indicate that autocrine growth factor Gas6 induces mesangial cell proliferation via latent transcription factor STAT3. Therefore, STAT3 might be a new therapeutic target for kidney disease induced by mesangial proliferation. Mesangial cell proliferation is essential for the pathogenesis and progression of glomerular disease. Previously, we showed that Gas6 plays a pivotal role in mesangial cell proliferation in vitro and in vivo. In the present study, we identified downstream targets of Gas6 signaling to examine the role in mesangial cell proliferation in vitro and in vivo. We found that Gas6 tyrosine phosphorylates STAT3 (signal transducers and activators of transcription) with concomitant translocation to the nucleus and induces STAT3-dependent transcriptional activation in cultured mesangial cells. Expressing dominant negative STAT3 inhibited Gas6-mediated transcriptional activation of STAT3 and abolished Gas6-induced mesangial cell proliferation. In a model of mesangial proliferative glomerulonephritis, STAT3 is phosphorylated in mesangial cells, and its phosphorylation peaks at day 8 after the injection of anti-Thy1.1 antibody. Inhibition of Gas6 by warfarin and the extracellular domain of its receptor, Axl, abolished phosphorylation of STAT3 in vivo. Thus, our in vitro and in vivo findings indicate that autocrine growth factor Gas6 induces mesangial cell proliferation via latent transcription factor STAT3. Therefore, STAT3 might be a new therapeutic target for kidney disease induced by mesangial proliferation. platelet-derived growth factor signal transducers and activators of transcription fluorescein isothiocyanate smooth muscle actin Dulbecco's modified Eagle's medium 5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside glomerulonephritis Mesangial cell proliferation is a characteristic feature of many types of glomerular diseases and is usually associated with matrix expansion, leading to the development of end stage kidney disease (1Fogo A. Ichikawa I. Semin. Nephrol. 1989; 9: 329-342PubMed Google Scholar, 2Striker L.J. Doi T. Elliot S. Striker G.E. Semin. Nephrol. 1989; 9: 318-328PubMed Google Scholar, 3Striker L.J. Peten E.P. Elliot S.J. Doi T. Striker G.E. Lab. Invest. 1991; 64: 446-456PubMed Google Scholar). Since the proliferation of mesangial cells is essential for the pathogenesis and progression of glomerular diseases, several studies have attempted to suppress mesangial cell proliferation by inhibiting specific mitogens, such as PDGF1 and basic fibroblast growth factor (4Johnson R.J. Raines E.W. Floege J. Yoshimura A. Pritzl P. Alpers C. Ross R. J. Exp. Med. 1992; 175: 1413-1416Crossref PubMed Scopus (354) Google Scholar, 5Floege J. Ostendorf T. Janssen U. Burg M. Radeke H.H. Vargeese C. Gill S.C. Green L.S. Janjic N. Am. J. Pathol. 1999; 154: 169-179Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 6Pichler R.H. Bassuk J.A. Hugo C. Reed M.J. Eng E. Gordon K.L. Pippin J. Alpers C.E. Couser W.G. Sage E.H. Johnson R.J. Am. J. Pathol. 1996; 148: 1153-1167PubMed Google Scholar). Among the mitogens for mesangial cells Gas6 is unique because its activation is vitamin K-dependent and is inhibited by the anticoagulant warfarin (7Manfioletti G. Brancolini C. Avanzi G. Schneider C. Mol. Cell. Biol. 1993; 13: 4976-4985Crossref PubMed Scopus (539) Google Scholar, 8Nakano T. Higashino K. Kikuchi N. Kishino J. Nomura K. Fujita H. Ohara O. Arita H. J. Biol. Chem. 1995; 270: 5702-5705Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). Recently we showed that Gas6 is an autocrine growth factor for mesangial cells (9Yanagita M. Ishii K. Ozaki H. Arai H. Nakano T. Ohashi K. Mizuno K. Kita T. Doi T. J. Am. Soc. Nephrol. 1999; 10: 2503-2509PubMed Google Scholar) and that warfarin and the extracellular domain of Axl (a receptor for Gas6) abolish mesangial cell proliferation by specific inhibition of the Gas6-mediated pathway in experimental glomerulonephritis (10Yanagita M. Arai H. Ishii K. Nakano T. Ohashi K. Mizuno K. Varnum B. Fukatsu A. Doi T. Kita T. Am. J. Pathol. 2001; 158: 1423-1432Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Moreover, administration of these agents abolishes the induction of PDGF-B in Thy1 GN. Thus, Gas6 seems to be not only a mitogen for mesangial cells, but also to play a crucial role in the progression of glomerular diseases by modulating the expression of other growth factors. It has been previously reported that constitutive activation of Eyk, a member of the Axl superfamily (11Besser D. Bromberg J.F. Darnell J.E. Hanafusa H. Mol. Cell. Biol. 1999; 19: 1401-1409Crossref PubMed Scopus (108) Google Scholar), results in cell transformation in vitro without significant stimulation of the Ras/ERK (extracellular signal-regulated kinase) pathway (11Besser D. Bromberg J.F. Darnell J.E. Hanafusa H. Mol. Cell. Biol. 1999; 19: 1401-1409Crossref PubMed Scopus (108) Google Scholar, 12Zong C. Yan R. August A. Darnell J.E. Hanafusa H. EMBO J. 1996; 15: 4515-4525Crossref PubMed Scopus (74) Google Scholar), which is activated by many oncogenes in the process of cell transformation (13Davis R.J. J. Biol. Chem. 1993; 268: 14553-14556Abstract Full Text PDF PubMed Google Scholar). The transforming activities of Eyk depend on phosphorylation of STAT3, a member of the STAT (signal transducers and activators of transcription) protein family. STAT proteins are latent transcription factors that become activated by phosphorylation of single tyrosine, which causes STAT proteins to dimerize. STAT dimerization is usually followed by translocation to the nucleus (14Decker T. Kovarik P. Cell. Mol. Life Sci. 1999; 55: 1535-1546Crossref PubMed Scopus (93) Google Scholar). Within the nucleus, STAT proteins recognize and bind to consensus DNA binding sites that represent enhancer sequences for a variety of genes, including the immediate early growth response genes. Activation of STAT proteins is often associated with differentiation and growth regulation. For example, STAT3 activation has been implicated in proliferation of cells (15Fukada T. Hibi M. Yamanaka Y. Takahashi-Tezuka M. Fujitani Y. Yamaguchi T. Nakajima K. Hirano T. Immunity. 1996; 5: 449-460Abstract Full Text Full Text PDF PubMed Scopus (586) Google Scholar), while STAT1 activation correlates with growth arrest of cells (16Bromberg J.F. Horvath C.M. Wen Z. Schreiber R.D. Darnell J.E. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 7673-7678Crossref PubMed Scopus (447) Google Scholar, 17Chin Y.E. Kitagawa M. Su W.C. You Z.H. Iwamoto Y. Fu X.Y. Science. 1996; 272: 719-722Crossref PubMed Scopus (743) Google Scholar). To elucidate molecular mechanisms of Gas6-mediated mesangial cell proliferation, we sought to identify downstream signaling components of the Gas6/Axl pathway essential for its various activities. In this study, we report that STAT3 is a key signaling molecule in Gas6-mediated mesangial cell proliferation in vitro and in vivo. This study reveals the crucial role of STAT3 activation in the pathogenesis of experimental glomerulonephritis. Anti-STAT3 and anti-phospho-STAT3 (Y705, 9131) polyclonal antibodies were from New England Biolabs (Beverly, MA). Horseradish peroxidase-conjugated goat anti-rabbit IgG and the enhanced chemiluminescent system were from Amersham Pharmacia Biotech (Buckinghamshire, United Kingdom). FITC- and rhodamine-labeled goat anti-rabbit IgG were from Chemicon International Inc. (Temecula, CA). Anti-Thy1.1 monoclonal antibody OX-7 was from Cedarlane (Hornby, Canada). Monoclonal antibody against α smooth muscle actin (αSMA) conjugated with FITC was from Sigma. Recombinant PDGF-BB protein was from Roche Molecular Biochemicals. Nitrocellulose filters were from Schleiecher & Schuell (Keene, NH). LAB-TEK chamber slides were from Nalgen Nunc International (Naperville, IL). LipofectAMINE Plus was from Life Technologies, Inc. OCT compound was from Miles Inc. (Elkhart, IN). A luciferase reporter construct for STAT3 (p4xM67-tk-Luc), expression vectors of wild type STAT3 and dominant negative STAT3, and the control vector ReCMV were kindly provided by Jackie Bromberg (The Rockefeller Univ.) (18Bromberg J.F. Horvath C.M. Besser D. Lathem W.W. Darnell J.E. Mol. Cell. Biol. 1998; 18: 2553-2558Crossref PubMed Scopus (572) Google Scholar). The constructs for recombinant Axl-Fc, Fc, and Gas6 were previously described (9Yanagita M. Ishii K. Ozaki H. Arai H. Nakano T. Ohashi K. Mizuno K. Kita T. Doi T. J. Am. Soc. Nephrol. 1999; 10: 2503-2509PubMed Google Scholar, 10Yanagita M. Arai H. Ishii K. Nakano T. Ohashi K. Mizuno K. Varnum B. Fukatsu A. Doi T. Kita T. Am. J. Pathol. 2001; 158: 1423-1432Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Renilla luciferase reporter construct, pRLCMV was from Promega (Madison, WI). Eight- to 12 week-old Wistar rats (180–200 g) were purchased from Shimizu Laboratory Animal Center (Hamamatsu, Japan). Rats were housed under specific pathogen-free conditions at the Animal Facilities of Kyoto University, Faculty of Medicine. All animal experiments were performed in accordance with institutional guidelines, and the Review Board of Kyoto University granted an ethical permission to this study. Mouse kidney mesangial cells were characterized and maintained as previously described (9Yanagita M. Ishii K. Ozaki H. Arai H. Nakano T. Ohashi K. Mizuno K. Kita T. Doi T. J. Am. Soc. Nephrol. 1999; 10: 2503-2509PubMed Google Scholar). Mesangial cells (106) were serum-starved in starving medium (0.5% bovine serum albumin/DMEM) for 48 h, medium was changed to serum-free DMEM, and cells were incubated for another 2 h. Mesangial cells were then stimulated with Gas6 for the indicated times. As a positive control, mesangial cells were stimulated with PDGF-BB for 10 min. After stimulation with Gas6 or PDGF-BB, mesangial cells were suspended in RIPA buffer (50 mm Tris, pH 7.5, 150 mm NaCl, 1% Nonidet P-40, 0.25% SDS, 1 mm Na3VO4, 2 mm EGTA, 1 mm phenylmethylsulfonyl fluoride, 10 μg/ml of aprotinin), and rotated for 1 h at 4 °C. After centrifugation of the samples, the supernatants were used as total cell lysates. Sixty μg of each sample was applied to SDS-polyacrylamide gel electrophoresis and immunoblotted. All experiments were repeated at least three times. Mesangial cells (104/well) plated in chamber slides were serum-starved and were stimulated with Gas6 for 10 min. After the stimulation, cells were fixed with phosphate-buffered saline containing 3% paraformaldehyde for 10 min at 4 °C and immunostained with anti-phospho-STAT3 antibody according to the manufacturer’s recommendation. Specimens were observed with a Zeiss microscope equipped with proper filters. Mesangial cells (5 × 105) were transfected with an expression vector encoding dominant negative STAT3 (1 μg) or a control vector, ReCMV (1 μg), luciferase reporter construct p4xM67-tk-Luc (0.5 μg), renilla luciferase reporter construct, pRLCMV (0.1 μg) by using LipofectAMINE Plus according to the manufacturer’s instructions. After 6 h of transfection, medium was changed to growth medium (60% DMEM, 20% F12, 20% fetal calf serum), and 3 h later medium was changed again to starving medium. After 48 h, medium was changed again to serum-free DMEM, and mesangial cells were incubated for another 2 h. After serum starvation, mesangial cells were stimulated with Gas6 for 8 h. Whole cell lysates of mesangial cells (10 μg) were subjected to luciferase assays according to the manufacturer’s instructions. Mesangial cells (0.5 × 105) were transfected with 1 μg of an expression vector encoding dominant negative STAT3 (18Bromberg J.F. Horvath C.M. Besser D. Lathem W.W. Darnell J.E. Mol. Cell. Biol. 1998; 18: 2553-2558Crossref PubMed Scopus (572) Google Scholar) or a control vector, ReCMV using LipofectAMINE Plus. After 6 h, medium was changed to growth medium and incubated for 4 h. After incubation in starving medium for 24 h, mesangial cells were stimulated with Gas6 or PDGF for 22 h and pulse-labeled with [3H]thymidine for 2 h, and incorporated [3H]thymidine was measured as previously described (9Yanagita M. Ishii K. Ozaki H. Arai H. Nakano T. Ohashi K. Mizuno K. Kita T. Doi T. J. Am. Soc. Nephrol. 1999; 10: 2503-2509PubMed Google Scholar). The transfection efficiency was about 60% by X-gal staining (not shown). Thy1 GN was induced by a single intravenous injection of mouse anti-Thy1.1 monoclonal antibody OX-7 (1 mg/kg body weight) as described elsewhere (19Nagasawa Y. Takenaka M. Matsuoka Y. Imai E. Hori M. Kidney Int. 2000; 57: 717-723Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 20Bokemeyer D. Ostendorf T. Kunter U. Lindemann M. Kramer H.J. Floege J. J. Am. Soc. Nephrol. 2000; 11: 232-240Crossref PubMed Google Scholar). Rats were sacrificed on days 0, 3, and were from the of rats using the R. K. A. C. J. Am. Soc. Nephrol. 1998; 9: Google Scholar, S.J. J. Invest. PubMed Scopus Google Scholar). The of the was Kidney were in in OCT compound and were using with polyclonal antibodies against of was by with monoclonal antibody against of the was by the antibody with of monoclonal antibodies or To the of for and was antibodies were incubated at 4 °C followed by the incubation with anti-rabbit was by the negative results of the antibodies with mouse monoclonal antibody or Specimens were observed with a Zeiss microscope equipped with proper filters. rats were with warfarin in (0.5 from days the of Thy1 GN to the days of as previously described (10Yanagita M. Arai H. Ishii K. Nakano T. Ohashi K. Mizuno K. Varnum B. Fukatsu A. Doi T. Kita T. Am. J. Pathol. 2001; 158: 1423-1432Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). In this rats were sacrificed on day and of was performed as previously described (9Yanagita M. Ishii K. Ozaki H. Arai H. Nakano T. Ohashi K. Mizuno K. Kita T. Doi T. J. Am. Soc. Nephrol. 1999; 10: 2503-2509PubMed Google Scholar). μg of recombinant was to rats a day from 24 h after the injection of antibodies to day (10Yanagita M. Arai H. Ishii K. Nakano T. Ohashi K. Mizuno K. Varnum B. Fukatsu A. Doi T. Kita T. Am. J. Pathol. 2001; 158: 1423-1432Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). In this rats were sacrificed on day were by and luciferase activities were by repeated of followed by the were are as was performed by using the CA). To elucidate the role of STAT3 in Gas6-mediated mesangial cell proliferation, we Gas6 STAT3 by its tyrosine phosphorylation and translocation to the nucleus in mouse mesangial cells. lysates of mesangial cells with the indicated of Gas6 for 10 min were with anti-phospho-STAT3 and polyclonal Gas6 phosphorylation of STAT3 in a and a at 1 In a tyrosine phosphorylation of STAT3 by of Gas6 by about and at 10 min 1 we Gas6-induced phosphorylation of STAT3 is by We mesangial cells with Gas6 with of the extracellular domain of Axl conjugated with the of Gas6-induced tyrosine phosphorylation of STAT3 was abolished by the of Gas6 with 1 that the phosphorylation of STAT3 is the binding of Gas6 to the cell We also phosphorylated STAT3 is to the nucleus in response to In was in mesangial cells 1 but in the 10 min after the stimulation with PDGF-BB also induced translocation of we Gas6 transcription in mesangial cells by the transcriptional activation of a reporter construct of the that is to STAT3 activation (18Bromberg J.F. Horvath C.M. Besser D. Lathem W.W. Darnell J.E. Mol. Cell. Biol. 1998; 18: 2553-2558Crossref PubMed Scopus (572) Google Scholar). were by the renilla luciferase activities of Mesangial cells transfected with control vector showed a in luciferase activities with while mesangial cells transfected with dominant negative STAT3 showed a inhibition of transcription induced by Gas6 Mesangial cells transfected with wild type STAT3 showed an in luciferase activities to that of control vector not shown). of mesangial cells transfected with dominant negative STAT3 was by the of in the and were not with that of mesangial cells transfected with control vector or wild type STAT3 not shown). PDGF-BB transcription by in mesangial cells as previously described C. Darnell J.E. 1995; 64: PubMed Scopus Google Scholar). To elucidate the role of STAT3 phosphorylation in Gas6-mediated cell proliferation, we Gas6-mediated cell proliferation on the phosphorylation of STAT3. Gas6 [3H]thymidine by in mesangial cells transfected with a control vector Gas6 not [3H]thymidine in the cells transfected with dominant negative STAT3, that STAT3 is in mesangial cell proliferation induced by In the cell proliferation by PDGF-BB was not by dominant negative STAT3. Since Gas6-mediated mesangial cell proliferation to depend on the phosphorylation of STAT3 in we the in vivo role of STAT3 phosphorylation in mesangial cell proliferation. We an model of mesangial proliferative glomerulonephritis as Thy1 glomerulonephritis (10Yanagita M. Arai H. Ishii K. Nakano T. Ohashi K. Mizuno K. Varnum B. Fukatsu A. Doi T. Kita T. Am. J. Pathol. 2001; 158: 1423-1432Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, Y. Takenaka M. Matsuoka Y. Imai E. Hori M. Kidney Int. 2000; 57: 717-723Abstract Full Text Full Text PDF PubMed Scopus (38) Google D. Ostendorf T. Kunter U. Lindemann M. Kramer H.J. Floege J. J. Am. Soc. Nephrol. 2000; 11: 232-240Crossref PubMed Google Scholar). In Thy1 mesangial cell proliferation at day peaks at day and by day after the injection of anti-Thy1.1 antibody (10Yanagita M. Arai H. Ishii K. Nakano T. Ohashi K. Mizuno K. Varnum B. Fukatsu A. Doi T. Kita T. Am. J. Pathol. 2001; 158: 1423-1432Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). we the phosphorylation of STAT3 in glomerular The glomerular proteins on days 0, 3, and were with and anti-phospho-STAT3 of STAT3 was on day but the of Thy1 with a on day 8 4 phosphorylation of STAT3 on day The expression of STAT3 protein was not changed the of was by of glomerular cells on day showed staining of 4 day 3, to be and the phosphorylation in with the of mesangial proliferation, on day and on day for and (a of activated mesangial R.J. H. Alpers C.E. P. Gordon K. J. Invest. 1991; PubMed Scopus Google Scholar) was to identify the cell types with staining of in the of and of kidney on day 8 that the of were by that of these positive cells be mesangial cells 4 we phosphorylation of STAT3 in glomerular proteins from Thy1 rats with warfarin or of STAT3 in Thy1 GN was inhibited by the administration of warfarin or the expression of STAT3 protein was not We also the by of kidney from rats with warfarin or showed staining of that without In this study, we have that STAT3 is a key signaling molecule in Gas6-mediated mesangial cell proliferation in vitro and in vivo. We have that Gas6 phosphorylates STAT3 on tyrosine and the phosphorylation of STAT3 is the cell receptor, We have also that Gas6 translocation of to the nucleus and tyrosine phosphorylation of STAT3 and translocation of are to be and for its activities M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), our that Gas6 the activation of STAT3 we have that Gas6-mediated mesangial cell proliferation on activation of STAT3. We have these in vitro to an in vivo model of glomerulonephritis. In Thy1 STAT3 is phosphorylated in the of glomerular cells. This phosphorylation the in mesangial cell proliferation and peaks at day 8 the expression of Gas6 as as mesangial cell proliferation of the cells with were to be mesangial cells. of the pathway by the administration of warfarin or inhibited the phosphorylation of STAT3 in as as the mesangial cell proliferation. Thus, our study has identified STAT3 as a signaling molecule in the development of glomerulonephritis and implicated as a target of the therapeutic for kidney disease. It is to that of the Gas6-mediated pathway in Thy1 GN inhibited the phosphorylation of STAT3 as as mesangial cell proliferation, other growth factors and J. N. K. Am. J. Kidney 1991; Full Text PDF PubMed Scopus Google Scholar, J. Eng E. Johnson R.J. Kidney Int. 1993; Google Scholar, R.J. Floege J. Couser W.G. Alpers C.E. J. Am. Soc. Nephrol. 1993; PubMed Google Scholar, J. Eng E. Alpers C.E. Johnson R.J. J. Invest. 1993; PubMed Scopus Google Scholar) present in Thy1 GN phosphorylation of STAT3 as Therefore, our findings indicate that Gas6-mediated STAT3 activation be of the in the development of Thy1 GN and that STAT3 is a signaling molecule of Gas6-mediated glomerular proliferation and might the development of glomerular diseases by modulating the expression of other growth factors. It be to study the role of Gas6 and STAT3 in a model of glomerulonephritis. As we showed in a Gas6 plays a crucial role in the development of glomerulonephritis, and the expression of Gas6 in the mesangial be a the activities of mesangial proliferation and glomerulonephritis (10Yanagita M. Arai H. Ishii K. Nakano T. Ohashi K. Mizuno K. Varnum B. Fukatsu A. Doi T. Kita T. Am. J. Pathol. 2001; 158: 1423-1432Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). In the present study, we have provided that STAT3 is another of mesangial cell proliferation, because phosphorylation of STAT3 is in with the of mesangial proliferation, and our study that the of STAT3 phosphorylation is in the in the to the of proliferation in Thy1 GN. results of of and indicate that the of mesangial cells are the sites of STAT3 Thus, our indicate that STAT3 is a pivotal of mesangial cell proliferation. Therefore, be to examine phosphorylation of STAT3 be in glomerulonephritis, such as and glomerulonephritis, and phosphorylation is to the and of glomerulonephritis. In mouse mesangial cells, the transfection efficiency was about 60% with LipofectAMINE not shown). the of about of cells, Gas6-mediated mesangial cell proliferation is inhibited by the transfection of dominant negative STAT3. This might be to the of factors from cells transfected with dominant negative STAT3 on the proliferation of cells. the other proliferative response to PDGF-BB was not by the transfection of dominant negative STAT3. Therefore, activation of STAT3 might not be for the activities of PDGF-BB in mesangial cells. Activation of STAT3 by Eyk is to after the binding of STAT3 via its domain to the present in and by tyrosine phosphorylation of STAT3 (11Besser D. Bromberg J.F. Darnell J.E. Hanafusa H. Mol. Cell. Biol. 1999; 19: 1401-1409Crossref PubMed Scopus (108) Google Scholar). sequences are also to be for STAT3 activation in several N. Z. Darnell J.E. Science. 1995; PubMed Scopus Google Darnell J.E. Schreiber R.D. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). Axl not but sequences are present in its domain A. B. C. R. Mol. Cell. Biol. 1991; 11: PubMed Scopus Google Scholar). we not the binding of STAT3 to Axl not shown). be because of the and binding of STAT3 and As in 1 was to the nucleus and not be in the The was at min after the of and not be min not shown). In our study an role for STAT3 in Gas6-mediated mesangial cell proliferation. to that inhibition of STAT3 activation in vivo the of mesangial cell proliferation. was that inhibition of STAT3 activation by the administration of dominant negative STAT3 results in of cell transformation and progression in vivo G. R. R. D. M. R. H. 1999; Google Scholar, Z. 2000; Google Scholar). A of the pathway a for new and specific targets for therapeutic in various kidney diseases associated with mesangial cell proliferation. We for of our We also Hori and for

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.