Ablation of p21-activated kinase-1 in mice promotes isoproterenol-induced cardiac hypertrophy in association with activation of Erk1/2 and inhibition of protein phosphatase 2A
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Earlier investigations in our lab indicated an anti-adrenergic effect induced by activation of p21-activated kinase (Pak-1) and protein phosphatase 2A (PP2A). Our objective was to test the hypothesis that Pak-1/PP2A is a signaling cascade controlling stress-induced cardiac growth. We determined the effects of ablation of the Pak-1 gene on the response of the myocardium to chronic stress of isoproterenol (ISO) administration. Wild-type (WT) and Pak-1-knockout (Pak-1-KO) mice were randomized into six groups to receive either ISO, saline (CTRL), or ISO and FR180204, a selective inhibitor of Erk1/2. Echocardiography revealed that hearts of the Pak-1-KO/ISO group had increased LV fractional shortening, reduced LV chamber volume in diastole and systole, increased cardiac hypertrophy, and enhanced transmitral early filling deceleration time, compared to all other groups. The changes were associated with an increase in relative Erk1/2 activation in Pak-1-KO/ISO mice versus all other groups. ISO-induced cardiac hypertrophy and Erk1/2 activation in Pak-1-KO/ISO were attenuated when the selective Erk1/2 inhibitor FR180204 was administered. Immunoprecipitation showed an association between Pak-1, PP2A, and Erk1/2. Cardiac myocytes infected with an adenoviral vector expressing constitutively active Pak-1 showed a repression of Erk1/2 activation. p38 MAPK phosphorylation was decreased in Pak-1-KO/ISO and Pak-1-KO/CTRL mice compared to WT. Levels of phosphorylated PP2A were increased in ISO-treated Pak-1-KO mice, indicating reduced phosphatase activity. Maximum Ca(2+)-activated tension in detergent-extracted bundles of papillary fibers from ISO-treated Pak-1-KO mice was higher than in all other groups. Analysis of cTnI phosphorylation indicated that compared to WT, ISO-induced phosphorylation of cTnI was blunted in Pak-1-KO mice. Active Pak-1 is a natural inhibitor of Erk1/2 and a novel anti-hypertrophic signaling molecule upstream of PP2A.
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Mouse cardiac troponin I is phosphorylated to a greater degree (only ~20-24% unphosphorylated) than human cTnI (~44-50% unphosphorylated).
“Mouse cardiac troponin I (cTnI) is phosphorylated to a greater degree (only ~20–24% un-phosphorylated) than its human counterpart (~44–50% un-phosphorylated)”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Taglieri, et al., 2011
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Zhang, S., Han, J., Sells, M. A., Chernoff, J., Knaus, U. G., Ulevitch, R. J., & Bokoch, G. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.41.23934 · Cited by 726 · see citing works
Self-citationBagrodia, S., Dérijard, B., Davis, R. J., & Cerione, R. A. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.47.27995 · Cited by 635 · see citing works
Sontag, E., Fedorov, S. A., Kamibayashi, C., Robbins, D. J., Cobb, M. H., & Mumby, M. C. (1993) · Cell · doi:10.1016/0092-8674(93)90533-v · Cited by 510 · see citing works
β-Arrestin–mediated β1-adrenergic receptor transactivation of the EGFR confers cardioprotection
Noma, T., Lemaire, A., Prasad, S. V. N., Barki‐Harrington, L., Tilley, D. G., Chen, J., Corvoisier, P. L., Violin, J. D., Wei, H., Lefkowitz, R. J., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31901 · Cited by 450 · see citing works
The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders
Aoki, Y., Niihori, T., Narumi, Y., Kure, S., & Matsubara, Y. (2008) · Human Mutation · doi:10.1002/humu.20748 · Cited by 360 · see citing works
Robertson, S. P., Johnson, J. D., Holroyde, M. J., Kranias, E. G., Potter, J. D., & Solaro, R. J. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)68355-9 · Cited by 357 · see citing works
Self-citationHunter, J. J., Tanaka, N., Rockman, H. A., Ross, J., & Chien, K. R. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.39.23173 · Cited by 312 · see citing works
Frost, J. A., Xu, S., Hutchison, M. R., Marcus, S., & Cobb, M. H. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.7.3707 · Cited by 275 · see citing works
Requirement of Rac1 in the development of cardiac hypertrophy
Satoh, M., Ogita, H., Takeshita, K., Mukai, Y., Kwiatkowski, D. J., & Liao, J. K. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510444103 · Cited by 271 · see citing works
Kehat, I., Davis, J., Tiburcy, M., Accornero, F., Saba-El-Leil, M. K., Maillet, M., York, A. J., Lorenz, J. N., Zimmermann, W., Meloche, S., et al. (2010) · Circulation Research · doi:10.1161/circresaha.110.231514 · Cited by 260 · see citing works
Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway
Brown, J. L., Stowers, L., Baer, M., et al. (1996) · Current Biology · doi:10.1016/s0960-9822(02)00546-8 · Cited by 252 · see citing works
MacDougall, L. K., Jones, L. R., & Cohen, P. (1991) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1991.tb15871.x · Cited by 233 · see citing works
Dual Effect of β-Adrenergic Receptors on Mitogen-activated Protein Kinase
Crespo, P., Cachero, T. G., Xu, N., & Gutkind, J. S. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.42.25259 · Cited by 223 · see citing works
Zamah, A. M., Delahunty, M. D., Luttrell, L. M., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202753200 · Cited by 195 · see citing works
Schmitt, J., & Stork, P. A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003213200 · Cited by 182 · see citing works
Davare, M. A., Horne, M. C., & Hell, J. W. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005462200 · Cited by 177 · see citing works
Akt Phosphorylation of Serine 21 on Pak1 Modulates Nck Binding and Cell Migration
Zhou, G.-L., Zhuo, Y., King, C. C., Fryer, B. H., Bokoch, G., & Field, J. M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.22.8058-8069.2003 · Cited by 168 · see citing works
Zou, Y., Yao, A., Zhu, W., Kudoh, S., Hiroi, Y., Shimoyama, M., Uozumi, H., Kohmoto, O., Takahashi, T., Shibasaki, F., et al. (2001) · Circulation · doi:10.1161/hc2601.090987 · Cited by 146 · see citing works
Method for isolation of adult mouse cardiac myocytes for studies of contraction and microfluorimetry
Wolska, B. M., & Solaro, R. J. (1996) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1996.271.3.h1250 · Cited by 139 · see citing works
Self-citationCardiac hypertrophy: Targeting Raf/MEK/ERK1/2-signaling
Lorenz, K., Schmitt, J. P., Vidal, M., & Lohse, M. J. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2009.08.002 · Cited by 125 · see citing works
Ueyama, T., Kawashima, S., Sakoda, T., Rikitake, Y., Ishida, T., Kawai, M., Yamashita, T., Ishido, S., Hotta, H., & Yokoyama, M. (2000) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.2000.1135 · Cited by 123 · see citing works
Ke, Y., Wang, Y. L., Pyle, W. G., et al. (2003) · Circulation Research · doi:10.1161/01.res.0000111522.02730.56 · Cited by 115 · see citing works
Self-citationRegulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes
Mao, K., Kobayashi, S., Jaffer, Z. M., et al. (2007) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2007.10.016 · Cited by 104 · see citing works
Buscemi, N., Foster, D. B., Neverova, I., & Eyk, J. E. V. (2002) · Circulation Research · doi:10.1161/01.res.0000035246.27856.53 · Cited by 92 · see citing works
PAK1-mediated activation of ERK1/2 regulates lamellipodial dynamics
Smith, S. D., Jaffer, Z. M., Chernoff, J., & Ridley, A. J. (2008) · Journal of Cell Science · doi:10.1242/jcs.027680 · Cited by 82 · see citing works
Self-citationWolska, B. M., Keller, R. S., Evans, C. C., et al. (1999) · Circulation Research · doi:10.1161/01.res.84.7.745 · Cited by 80 · see citing works
Self-citationCdc42 is an antihypertrophic molecular switch in the mouse heart
Maillet, M., Lynch, J. M., Sanna, B., York, A. J., Zheng, Y., & Molkentin, J. D. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37694 · Cited by 77 · see citing works
The role of PAK-1 in activation of MAP kinase cascade and oncogenic transformation by Akt
Somanath, P. R., Vijai, J., Kichina, J. V., et al. (2009) · Oncogene · doi:10.1038/onc.2009.114 · Cited by 63 · see citing works
Kirk, J. A., MacGowan, G. A., Evans, C. S., Smith, S. H., Warren, C. M., Mamidi, R., Chandra, M., Stewart, A. F. R., Solaro, R. J., & Shroff, S. G. (2009) · Circulation Research · doi:10.1161/circresaha.109.205427 · Cited by 56 · see citing works
Self-citationKe, Y., Lei, M., Collins, T. P., et al. (2007) · Circulation Research · doi:10.1161/01.res.0000266742.51389.a4 · Cited by 54 · see citing works
Self-citationSheehan, K. A., Ke, Y., Wolska, B. M., & Solaro, R. J. (2008) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00012.2008 · Cited by 43 · see citing works
Self-citationp21-Activated kinase-1 and its role in integrated regulation of cardiac contractility
Sheehan, K. A., Ke, Y., & Solaro, R. J. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00253.2007 · Cited by 43 · see citing works
Self-citationHuebert, R. C., Li, Q., Adhikari, N., Charles, N. J., Han, X., Ezzat, M.-K., Grindle, S. M., Park, S., Ormaza, S., Fermin, D. R., et al. (2004) · Physiological Genomics · doi:10.1152/physiolgenomics.00098.2004 · Cited by 41 · see citing works
Barros, F., Mieskes, G., del Camino, D., & de la Peña, P. (1993) · FEBS Letters · doi:10.1016/0014-5793(93)80851-k · Cited by 27 · see citing works
Solis, R. S., Ge, Y., & Walker, J. W. (2011) · Protein Science · doi:10.1002/pro.623 · Cited by 26 · see citing works
Multi-Gram Scale Synthesis of FR180204
Patnaik, S., Dietz, H. C., Zheng, W., Austin, C. P., & Marugán, J. (2009) · The Journal of Organic Chemistry · doi:10.1021/jo901835m · Cited by 22 · see citing works
Novel bradykinin signaling in adult rat cardiac myocytes through activation of p21-activated kinase
Ke, Y., Sheehan, K. A., Egom, E. E. A., et al. (2010) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01070.2009 · Cited by 15 · see citing works
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Small and large animal models in cardiac contraction research: advantages and disadvantages
Milani-Nejad, N., & Janssen, P. M. L. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.10.007 · Cited by 484 · see citing works
- Authors
- Taglieri, D. M., Monasky, M. M., Knezevic, I., Sheehan, K. A., Lei, M., Wang, X., Chernoff, J., Wolska, B. M., Ke, Y., & Solaro, R. J.
- Affiliations
- University of Illinois Chicago (US)
- Manchester Academic Health Science Centre (GB)
- University of Manchester (GB)
- Fox Chase Cancer Center (US)
- Corresponding author
- Taglieri, Domenico M.
- Monasky, Michelle M.
- Knezevic, Ivana
- Sheehan, Katherine A.
- Lei, Ming
- Wang, Xin
- Chernoff, Jonathan
- Wolska, Beata M.
- Ke, Yunbo
- Solaro, R. John
- ORCID
- Venue
- Journal of Molecular and Cellular Cardiology
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 51
- Issue
- 6
- Pages
- 988-996
- ISSN
- 0022-2828 (ISSN-L)
- PMC
- PMC3208757
- OpenAlex
- W1965261716
- Cited by
- 62
- References
- 37
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 5 · 2015: 4 · 2014: 9 · 2013: 9 · 2012: 6
- FWCI
- 5.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Molecular and Cellular Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- British Heart Foundation (PG/09/052/27833, PG/12/76/29852)
- National Heart, Lung, and Blood Institute (T32 HL-07692-16-20, R01 HL 64035, R01HL064035, T32HL007692, P01HL062426)
- National Center for Research Resources (UL1RR029879)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- PAK1, protein phosphatase 2A, ERK1/2, cardiac hypertrophy, isoproterenol, p38 MAPK, troponin I phosphorylation, calcium-activated tension
- MeSH terms
- Animals, Calcium, Disease Models, Animal, Echocardiography, Enzyme Activation, Female, Cardiomegaly, Isoproterenol, Male, Myofibrils, Phosphorylation, Pyrazoles, Pyridazines, Signal Transduction, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Myocytes, Cardiac, Protein Kinase Inhibitors, Extracellular Signal-Regulated MAP Kinases, Mitogen-Activated Protein Kinase 3, Mice, p21-Activated Kinases, Protein Phosphatase 2, Gene Knockout Techniques
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