{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:20:42Z","timestamp":1760059242817,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:00:00Z","timestamp":1748563200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Australia Award"},{"name":"Swinburne University postgraduate scholarship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Advances in microfluidics, optogenetics and electronics have enabled the study of dynamically controlled inputs on cellular fate. Here, we applied a microfluidic system to deliver periodic inputs of growth factors to pheochromocytoma cells and measured the extent of premature differentiation as a function of input frequency. Epidermal growth factor-triggered differentiation peaked at two cycles\/hour, while nerve growth factor-triggered differentiation peaked at one cycle\/hour. To interpret the results, we analyzed a published model that attributed pheochromocytoma cell differentiation to the linear combination of activated enzymes extracellular signal-regulated kinase (ERK), cAMP response element binding protein (CREB), protein kinase B (AKT) and c-Jun N-terminal kinase (JNK) at specific times after step input stimulation. Transfer functions for enzyme activation were derived from the published time-domain activation kinetics and these transfer functions were combined in a parallel architecture as a predictor of neurite outgrowth, as a function of input frequency. Qualitative agreement was observed between the model and the experiments.<\/jats:p>","DOI":"10.3390\/ijms26115287","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T11:40:32Z","timestamp":1748864432000},"page":"5287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Frequency-Dependent Premature Differentiation of Pheochromocytoma Cells Exhibits Band-Pass Filter Behavior Correlation with Intracellular Enzyme Activation Kinetics"],"prefix":"10.3390","volume":"26","author":[{"given":"Zubaidah","family":"Ningsih","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Mathematics and Natural Sciences, Brawijaya University, Jl. Veteran, Malang 65145, Indonesia"},{"name":"Department of Physics and Astronomy, Optical Sciences Centre, School of Science, Computing and Emerging Technologies, Swinburne University of Technology, Melbourne, VIC 3122, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2746-4193","authenticated-orcid":false,"given":"Nguyen H. N.","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering and Mechanics, Drexel University, Philadelphia, PA 19094, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6182-3049","authenticated-orcid":false,"given":"Andrew H. A.","family":"Clayton","sequence":"additional","affiliation":[{"name":"Department of Physics and Astronomy, Optical Sciences Centre, School of Science, Computing and Emerging Technologies, Swinburne University of Technology, Melbourne, VIC 3122, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/0092-8674(95)90401-8","article-title":"Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation","volume":"80","author":"Marshall","year":"1995","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.coisb.2016.12.003","article-title":"An operational view of intercellular signaling pathways","volume":"1","author":"Antebi","year":"2017","journal-title":"Curr. Opin. Syst. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1126\/science.1239999","article-title":"Functional roles of pulsing in genetic circuits","volume":"342","author":"Levine","year":"2013","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1126\/science.1071914","article-title":"The IkappaB-NF-kappaB signaling module: Temporal control and selective gene activation","volume":"298","author":"Hoffmann","year":"2002","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1038\/s41467-021-21562-0","article-title":"Quantifying information accumulation encoded in the dynamics of biochemical signaling","volume":"12","author":"Tang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1126\/science.1218351","article-title":"P53 dynamics control cell fate","volume":"336","author":"Purvis","year":"2012","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.devcel.2014.05.022","article-title":"Encoding of temporal signals by the TGF-\u03b2 pathway and implications for embryonic patterning","volume":"30","author":"Sorre","year":"2014","journal-title":"Dev. Cell"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jovic, A., Howell, B., Cote, M., Wade, S.M., Mehta, K., Miyawaki, A., Neubig, R.R., Linderman, J.J., and Takayama, S. (2010). Phase-locked signals elucidate circuit architecture of an oscillatory pathway. PLoS Comput. Biol., 6.","DOI":"10.1371\/journal.pcbi.1001040"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1038\/nsmb.3452","article-title":"P53 pulses lead to distinct patterns of gene expression albeit similar DNA-binding dynamics","volume":"24","author":"Hafner","year":"2017","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Hansen, A.S., and O\u2019Shea, E.K. (2013). Promoter decoding of transcription factor dynamics involves a trade-off between noise and control of gene expression. Mol. Syst. Biol., 9.","DOI":"10.1038\/msb.2013.56"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Harton, M.D., Koh, W.S., Bunker, A.D., Singh, A., and Batchelor, E. (2019). P53 pulse modulation differentially regulates target gene promoters to regulate cell fate decisions. Mol. Syst. Biol., 15.","DOI":"10.15252\/msb.20188685"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1016\/j.immuni.2021.04.011","article-title":"Six distinct NF\u03baB signaling codons convey discrete information to distinguish stimuli and enable appropriate macrophage responses","volume":"54","author":"Adelaja","year":"2021","journal-title":"Immunity"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e09100","DOI":"10.7554\/eLife.09100","article-title":"NF-\u03baB oscillations translate into functionally related patterns of gene expression","volume":"5","author":"Zambrano","year":"2016","journal-title":"eLife"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e06559","DOI":"10.7554\/eLife.06559","article-title":"Limits on information transduction through amplitude and frequency regulation of transcription factor activity","volume":"4","author":"Hansen","year":"2015","journal-title":"eLife"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"ra76","DOI":"10.1126\/scisignal.2002983","article-title":"The Temporal Pattern of Stimulation Determines the Extent and Duration of MAPK Activation in a Caenorhabditis elegans Sensory Neuron","volume":"5","author":"Tomida","year":"2012","journal-title":"Sci. Signal."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1039\/C5IB00156K","article-title":"Measurement of the entrainment window of islets of Langerhans by microfluidic delivery of a chirped glucose waveform","volume":"7","author":"Dhumpa","year":"2015","journal-title":"Integr. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1016\/j.bpj.2014.04.015","article-title":"Negative feedback synchronizes islets of Langerhans","volume":"106","author":"Dhumpa","year":"2014","journal-title":"Biophys. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/nature09145","article-title":"Single-cell NF-kappaB dynamics reveal digital activation and analogue information processing","volume":"466","author":"Tay","year":"2010","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1039\/c1mb05031a","article-title":"Hi-Fi transmission of periodic signals amid cell-to-cell variability","volume":"7","author":"Jovic","year":"2011","journal-title":"Mol. Biosyst."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.cell.2015.01.013","article-title":"Noise facilitates transcriptional control under dynamic inputs","volume":"160","author":"Kellogg","year":"2015","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1126\/science.1164860","article-title":"Pulsatile stimulation determines timing and specificity of NF-kappaB-dependent transcription","volume":"324","author":"Ashall","year":"2009","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1039\/C6IB00178E","article-title":"New insights into mammalian signaling pathways using microfluidic pulsatile inputs and mathematical modeling","volume":"9","author":"Sumit","year":"2017","journal-title":"Integr. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Tran, N.H.N., and Clayton, A.H.A. (2023). Transfer function approach to understanding periodic forcing of signal transduction networks. Phys. Biol., 20.","DOI":"10.1088\/1478-3975\/acc300"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1126\/science.1151582","article-title":"The Frequency Dependence of Osmo-Adaptation in Saccharomyces cerevisiae","volume":"319","author":"Mettetal","year":"2008","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1126\/science.aab0892","article-title":"Oscillatory stress stimulation uncovers an Achilles\u2019 heel of the yeast MAPK signaling network","volume":"350","author":"Mitchell","year":"2015","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ningsih, Z., and Clayton, A.H.A. (2020). Does frequency-dependent cell proliferation exhibit a Fano-type resonance?. Phys. Biol., 17.","DOI":"10.1088\/1478-3975\/ab9242"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ryu, H., Chung, M., Dobrzy\u0144ski, M., Fey, D., Blum, Y., Sik Lee, S., Peter, M., Kholodenko, B.N., Li Jeon, N., and Pertz, O. (2015). Frequency modulation of ERK activation dynamics rewires cell fate. Mol. Syst. Biol., 11.","DOI":"10.15252\/msb.20156458"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.molcel.2012.11.002","article-title":"Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals","volume":"49","author":"Albeck","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"eaao3048","DOI":"10.1126\/science.aao3048","article-title":"Cancer mutations and targeted drugs can disrupt dynamic signal encoding by the Ras-Erk pathway","volume":"361","author":"Bugaj","year":"2018","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.devcel.2020.09.013","article-title":"Cell-Cycle-Dependent ERK Signaling Dynamics Direct Fate Specification in the Mammalian Preimplantation Embryo","volume":"55","author":"Pokrass","year":"2020","journal-title":"Dev. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e60541","DOI":"10.7554\/eLife.60541","article-title":"MAPK activity dynamics regulate non-cell autonomous effects of oncogene expression","volume":"9","author":"Aikin","year":"2020","journal-title":"eLife"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.cels.2020.02.005","article-title":"A Live-Cell Screen for Altered Erk Dynamics Reveals Principles of Proliferative Control","volume":"10","author":"Goglia","year":"2020","journal-title":"Cell Syst."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.devcel.2019.01.009","article-title":"Signaling Dynamics Control Cell Fate in the Early Drosophila Embryo","volume":"48","author":"Johnson","year":"2019","journal-title":"Dev. Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1016\/j.devcel.2023.04.013","article-title":"Optogenetic manipulation identifies the roles of ERK and AKT dynamics in controlling mouse embryonic stem cell exit from pluripotency","volume":"58","author":"Arekatla","year":"2023","journal-title":"Dev. Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1126\/science.aay8241","article-title":"Temporal integration of mitogen history in mother cells controls proliferation of daughter cells","volume":"368","author":"Min","year":"2020","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1016\/j.devcel.2021.05.007","article-title":"Collective ERK\/Akt activity waves orchestrate epithelial homeostasis by driving apoptosis-induced survival","volume":"56","author":"Gagliardi","year":"2021","journal-title":"Dev. Cell"},{"key":"ref_37","unstructured":"Ningsih, Z. (2017). How Do Cells Process Information?. [Ph.D. Thesis, Swinburne University of Technology]."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Akimoto, Y., Yugi, K., Uda, S., Kudo, T., Komori, Y., Kubota, H., and Kuroda, S. (2013). The Extraction of Simple Relationships in Growth Factor-Specific Multiple-Input and Multiple-Output Systems in Cell-Fate Decisions by Backward Elimination PLS Regression. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072780"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1039\/c003921g","article-title":"Structure of the egf receptor transactivation circuit integrates multiple signals with cell context","volume":"6","author":"Joslin","year":"2010","journal-title":"Mol. BioSyst."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"58","DOI":"10.3934\/biophy.2015.2.58","article-title":"A Microfluidic Device for Spatiotemporal Delivery of Stimuli to Cells","volume":"2","author":"Ningsih","year":"2015","journal-title":"Aims Biophys."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Tran, N.H.N., Frascoli, F., and Clayton, A.H.A. (2025). A Frequency Domain Analysis of the Growth Factor-Driven Extra-Cellular-Regulated Kinase (ERK) Pathway. Biology, 14.","DOI":"10.3390\/biology14040374"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Stern, A.D., Smith, G.R., Santos, L.C., Sarmah, D., Zhang, X., Lu, X., Iuricich, F., Pandey, G., Iyengar, R., and Birtwistle, M.R. (2022). Relating individual cell division events to single-cell ERK and Akt activity time courses. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-23071-6"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"103240","DOI":"10.1016\/j.isci.2021.103240","article-title":"Electrically synchronizing and modulating the dynamics of ERK activation to regulate cell fate","volume":"24","author":"Guo","year":"2021","journal-title":"iScience"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/11\/5287\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:44:14Z","timestamp":1760031854000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/11\/5287"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,30]]},"references-count":43,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ijms26115287"],"URL":"https:\/\/doi.org\/10.3390\/ijms26115287","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,5,30]]}}}