{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T13:49:24Z","timestamp":1760622564053},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2007,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Computational models of cell signaling networks typically are aimed at capturing dynamics of molecular components to derive quantitative insights from prior experimental data, and to make predictions concerning altered dynamics under different conditions. However, signaling network models have rarely been used to predict how cell phenotypic behaviors result from the integrated operation of these networks. We recently developed a decision tree model for how EGF-induced fibroblast cell motility across two-dimensional fibronectin-coated surfaces depends on the integrated activation status of five key signaling nodes, including a proximal regulator of transcellular contractile force generation, MLC (myosin light chain) [Hautaniemi <jats:italic>et al<\/jats:italic>, Bioinformatics 21: 2027 {2005}], but we have not previously attempted predictions of new experimental effects from this model.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>In this new work, we construct an improved decision tree model for the combined influence of EGF and fibronectin on fibroblast cell migration based on a wider spectrum of experimental protein signaling and cell motility measurements, and directly test a significant and non-intuitive <jats:italic>a priori<\/jats:italic> prediction for the outcome of a targeted molecular intervention into the signaling network: that partially reducing activation of MLC would increase cell motility on moderately adhesive surfaces. This prediction was indeed confirmed experimentally: partial inhibition of the activating MLC kinase (MLCK) upstream using the pharmacologic agent ML-7 resulted in increased motility of NR6 fibroblasts. We further extended this exciting finding by showing that partial reduction of MLC activation similarly enhanced the transmigration of the human breast carcinoma cell line MDA-213 through a Matrigel barrier.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>These findings specifically highlight a central regulatory role for transcellular contractility in governing cell motility, while at the same time demonstrating the value of a decision tree approach to a systems \"signal-response\" model in discerning non-intuitive behavior arising from integrated operation a cell signaling network.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-1-9","type":"journal-article","created":{"date-parts":[[2007,2,13]],"date-time":"2007-02-13T19:09:49Z","timestamp":1171393789000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Decision tree modeling predicts effects of inhibiting contractility signaling on cell motility"],"prefix":"10.1186","volume":"1","author":[{"given":"Sourabh","family":"Kharait","sequence":"first","affiliation":[]},{"given":"Sampsa","family":"Hautaniemi","sequence":"additional","affiliation":[]},{"given":"Shan","family":"Wu","sequence":"additional","affiliation":[]},{"given":"Akihiro","family":"Iwabu","sequence":"additional","affiliation":[]},{"given":"Douglas A","family":"Lauffenburger","sequence":"additional","affiliation":[]},{"given":"Alan","family":"Wells","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2007,1,29]]},"reference":[{"key":"9_CR1","doi-asserted-by":"publisher","first-page":"2027","DOI":"10.1093\/bioinformatics\/bti278","volume":"21","author":"S Hautaniemi","year":"2005","unstructured":"Hautaniemi S, Kharait S, Iwabu A, Wells A, Lauffenburger DA: Modeling and prediction of signal transduction cascades using decision trees. Bioinformatics. 2005, 21: 2027-2035. 10.1093\/bioinformatics\/bti278","journal-title":"Bioinformatics"},{"issue":"1","key":"9_CR2","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.cbpa.2005.12.016","volume":"10","author":"KA Janes","year":"2006","unstructured":"Janes KA, Lauffenburger DA: A biological approach to computational models of proteomic networks. Current Opinion in Chemical Biology. 2006, 10 (1): 73-80. 10.1016\/j.cbpa.2005.12.016","journal-title":"Current Opinion in Chemical Biology"},{"issue":"2","key":"9_CR3","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1080\/028418602753669481","volume":"41","author":"A Wells","year":"2002","unstructured":"Wells A, Kassis J, Solava J, Turner T, Lauffenburger DA: Growth factor-induced cell motility in tumor invasion. Acta Oncologica. 2002, 41 (2): 124-130. 10.1080\/028418602753669481","journal-title":"Acta Oncologica"},{"key":"9_CR4","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/S0065-230X(08)61023-4","volume":"78","author":"A Wells","year":"2000","unstructured":"Wells A: Tumor invasion: role of growth factor-induced cell motility. Advances in Cancer Research. 2000, 78: 31-101.","journal-title":"Advances in Cancer Research"},{"issue":"5","key":"9_CR5","first-page":"302","volume":"1","author":"JC Barrett","year":"2003","unstructured":"Barrett JC, Bennett LM, Fleming LK, Linehan WM, Liotta LA, Rosenberg SA, Petricoin EF, Staudt LM, Thompson TE, Yang JC: Linking laboratory and clinical research: the development of molecularly targeted therapeutics inside the national cancer institute center for cancer research. Clin Adv Hematol Oncol. 2003, 1 (5): 302-306.","journal-title":"Clin Adv Hematol Oncol"},{"issue":"17","key":"9_CR6","doi-asserted-by":"publisher","first-page":"2623","DOI":"10.1016\/j.ejca.2004.05.020","volume":"40","author":"J Wulfkuhle","year":"2004","unstructured":"Wulfkuhle J, Espina V, Liotta L, Petricoin E: Genomic and proteomic technologies for individualisation and improvement of cancer treatment. Eur J Cancer. 2004, 40 (17): 2623-2632. 10.1016\/j.ejca.2004.05.020","journal-title":"Eur J Cancer"},{"issue":"5651","key":"9_CR7","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1126\/science.1092053","volume":"302","author":"AJ Ridley","year":"2003","unstructured":"Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, Parsons JT, Horwitz AR: Cell migration: integrating signals from front to back. Science. 2003, 302 (5651): 1704-1709. 10.1126\/science.1092053","journal-title":"Science"},{"issue":"3","key":"9_CR8","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1016\/S0092-8674(00)81280-5","volume":"84","author":"DA Lauffenburger","year":"1996","unstructured":"Lauffenburger DA, Horwitz AF: Cell migration: a physically integrated molecular process. Cell. 1996, 84 (3): 359-369. 10.1016\/S0092-8674(00)81280-5","journal-title":"Cell"},{"key":"9_CR9","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1146\/annurev.bioeng.2.1.31","volume":"2","author":"AR Asthagiri","year":"2000","unstructured":"Asthagiri AR, Lauffenburger DA: Bioengineering models of cell signaling. Annu Rev Biomed Eng. 2000, 2: 31-53. 10.1146\/annurev.bioeng.2.1.31","journal-title":"Annu Rev Biomed Eng"},{"key":"9_CR10","doi-asserted-by":"publisher","first-page":"2814","DOI":"10.1016\/S0006-3495(99)77435-7","volume":"76","author":"G Maheshwari","year":"1999","unstructured":"Maheshwari G, Wells A, Griffith LG, Lauffenburger DA: Biophysical integration of effects of epidermal growth factor and fibronectin on fibroblast migration. Biophysical Journal. 1999, 76: 2814-2823.","journal-title":"Biophysical Journal"},{"issue":"3","key":"9_CR11","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1083\/jcb.122.3.729","volume":"122","author":"PA DiMilla","year":"1993","unstructured":"DiMilla PA, Stone JA, Quinn JA, Albelda SM, Lauffenburger DA: Maximal migration of human smooth muscle cells on fibronectin and type IV collagen occurs at an intermediate attachment strength. J Cell Biol. 1993, 122 (3): 729-737. 10.1083\/jcb.122.3.729","journal-title":"J Cell Biol"},{"key":"9_CR12","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1242\/jcs.111.16.2423","volume":"111","author":"MF Ware","year":"1998","unstructured":"Ware MF, Wells A, Lauffenburger DA: Epidermal growth factor alters fibroblast migration speed and directional persistence reciprocally and in matrix-dependent manner. J Cell Sci. 1998, 111: 2423-2432.","journal-title":"J Cell Sci"},{"key":"9_CR13","doi-asserted-by":"publisher","first-page":"14551","DOI":"10.1074\/jbc.M311981200","volume":"279","author":"A Iwabu","year":"2004","unstructured":"Iwabu A, Smith K, Allen FD, Lauffenburger DA, Wells A: EGF induces fibroblast contractility and motility via a PKCd-dependent pathway. J Biol Chem. 2004, 279: 14551-14560. 10.1074\/jbc.M311981200","journal-title":"J Biol Chem"},{"issue":"2","key":"9_CR14","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1083\/jcb.200309056","volume":"165","author":"S Komatsu","year":"2004","unstructured":"Komatsu S, Ikebe M: ZIP kinase is responsible for the phosphorylation of myosin II and necessary for cell motility in mammalian fibroblasts. J Cell Biol. 2004, 165 (2): 243-254. 10.1083\/jcb.200309056","journal-title":"J Cell Biol"},{"issue":"6","key":"9_CR15","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1096\/fj.03-0979rev","volume":"18","author":"DN Jackson","year":"2004","unstructured":"Jackson DN, Foster DA: The enigmatic protein kinase Cd: complex roles in cell proliferation and survival. Faseb Journal. 2004, 18 (6): 627-636. 10.1096\/fj.03-0979rev","journal-title":"Faseb Journal"},{"issue":"2","key":"9_CR16","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/0304-3835(95)04066-8","volume":"99","author":"BJ Long","year":"1996","unstructured":"Long BJ, Rose DP: Invasive capacity and regulation of urokinase-type plasminogen activator in estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells, and a transfectant (S30) stably expressing ER. Cancer Letters. 1996, 99 (2): 209-215. 10.1016\/0304-3835(95)04066-8","journal-title":"Cancer Letters"},{"issue":"9","key":"9_CR17","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1038\/nrd891","volume":"1","author":"EF Petricoin","year":"2002","unstructured":"Petricoin EF, Zoon KC, Kohn EC, Barrett JC, Liotta LA: Clinical proteomics: translating benchside promise into bedside reality. Nature Reviews - Drug Discovery. 2002, 1 (9): 683-695. 10.1038\/nrd891","journal-title":"Nature Reviews - Drug Discovery"},{"issue":"1","key":"9_CR18","first-page":"69","volume":"7","author":"VE Bichsel","year":"2001","unstructured":"Bichsel VE, Liotta LA, Petricoin EF: Cancer proteomics: from biomarker discovery to signal pathway profiling. Cancer Journal. 2001, 7 (1): 69-78.","journal-title":"Cancer Journal"},{"key":"9_CR19","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1111\/j.1067-1927.2004.012302.x","volume":"12","author":"KT Tran","year":"2004","unstructured":"Tran KT, Griffith LG, Wells A: Extracellular matrix signaling through growth factor receptors during wound healing. Wound Repair and Regeneration. 2004, 12: 262-268. 10.1111\/j.1067-1927.2004.012302.x.","journal-title":"Wound Repair and Regeneration"},{"issue":"2","key":"9_CR20","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1083\/jcb.200103103","volume":"154","author":"CS Swindle","year":"2001","unstructured":"Swindle CS, Tran K, Johnson TD, Banerjee P, Mayes AM, Griffith LG, Wells A: Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor. J Cell Biol. 2001, 154 (2): 459-468. 10.1083\/jcb.200103103","journal-title":"J Cell Biol"},{"issue":"26","key":"9_CR21","doi-asserted-by":"publisher","first-page":"23341","DOI":"10.1074\/jbc.M008847200","volume":"276","author":"A Glading","year":"2001","unstructured":"Glading A, Uberall F, Keyse SM, Lauffenburger DA, Wells A: Membrane proximal ERK signaling is required for M-calpain activation downstream of epidermal growth factor receptor signaling. J Biol Chem. 2001, 276 (26): 23341-23348. 10.1074\/jbc.M008847200","journal-title":"J Biol Chem"},{"key":"9_CR22","doi-asserted-by":"publisher","first-page":"23341","DOI":"10.1074\/jbc.M008847200","volume":"276","author":"A Glading","year":"2001","unstructured":"Glading A, Uberall F, Keyse SM, Lauffenburger DA, Wells A: Membrane proximal ERK signaling is required for M-calpain activation downstream of EGF receptor signaling. J Biol Chem. 2001, 276: 23341-23348. 10.1074\/jbc.M008847200","journal-title":"J Biol Chem"},{"key":"9_CR23","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1038\/385537a0","volume":"385","author":"SP Palecek","year":"1997","unstructured":"Palecek SP, Loftus JC, Ginsburg MH, Lauffenburger DA, Horwitz AF: Integrin-ligand binding properties govern cell migration speed through cell-substratum adhesiveness. Nature. 1997, 385: 537-540. 10.1038\/385537a0","journal-title":"Nature"},{"key":"9_CR24","volume-title":"Classification and Regression Trees","author":"L Breiman","year":"1984","unstructured":"Breiman L, Friedman JH, Olshen RA, Stone CJ: Classification and Regression Trees. 1984, Wadsworth"},{"issue":"7","key":"9_CR25","doi-asserted-by":"publisher","first-page":"2537","DOI":"10.1109\/18.887861","volume":"46","author":"J Rissanen","year":"2000","unstructured":"Rissanen J: MDL denoising. IEEE Transactions on Information Theory. 2000, 46 (7): 2537-2543. 10.1109\/18.887861.","journal-title":"IEEE Transactions on Information Theory"},{"key":"9_CR26","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1109\/TIT.1982.1056489","volume":"IT-28","author":"S Lloyd","year":"1982","unstructured":"Lloyd S: Least square quantization in PCM. IEEE Trans Information Theory. 1982, IT-28: 129-137. 10.1109\/TIT.1982.1056489.","journal-title":"IEEE Trans Information Theory"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-1-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T02:59:45Z","timestamp":1630465185000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-1-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,1,29]]},"references-count":26,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2007,12]]}},"alternative-id":["9"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-1-9","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,1,29]]},"assertion":[{"value":"9 October 2006","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 January 2007","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 January 2007","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"9"}}