{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T11:03:58Z","timestamp":1784891038896,"version":"3.55.0"},"reference-count":55,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T00:00:00Z","timestamp":1736121600000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The proliferation of CAR\u2010T cells was hindered and cannot play its killing function well in solid tumors. And yet the regulatory mechanism of CAR\u2010T cell proliferation is not fully understood. Here, we showed that recombinant expression of CD19CAR in T cells significantly increased the basal activation level of CAR\u2010T cells and LCK activation. Both LCK and SMAD4 were essential for CAR\u2010T cells proliferation since over\u2010express LCK or SMAD4 significantly promotes CAR\u2010T cells proliferation, while knock\u2010down LCK or SMAD4 expression inhibited the proliferation of CAR\u2010T cells seriously. More cells go into apoptosis when knock\u2010down LCK or SMAD4 expression, and the cell cycle was arrested in G2\/M or S phase, respectively. Over\u2010express LCK or SMAD4 significantly promotes phosphorylation of PI3K and Akt, while it was inhibited when cells were treated with PI3K and Akt inhibitors (LY294002 or MK2206). Further mechanism exploration experiments showed that SMAD4 bound on the promoter region of LCK regulating its expression. Taken together, we reported that the transcription factor SMAD4 regulated the expression of LCK and further involved in the PI3K\/Akt signaling pathway to affect the proliferation of CAR\u2010T cells.<\/jats:p>","DOI":"10.1002\/jcp.31520","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T07:17:34Z","timestamp":1736234254000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["SMAD4 Regulates the Expression of LCK\u00a0Affecting Chimeric Antigen Receptor\u2010T Cells Proliferation Through PI3K\/Akt Signaling Pathway"],"prefix":"10.1002","volume":"240","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2048-0665","authenticated-orcid":false,"given":"Rongxue","family":"Wan","sequence":"first","affiliation":[{"name":"Department of Transfusion Medicine, School of Biotechnology Southern Medical University  Guangzhou Guangdong China"},{"name":"Guangzhou Blood Center, Institute of Blood Transfusion and Hematology Guangzhou Medical University  Guangzhou Guangdong China"},{"name":"Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Fu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences Southern Medical University  Guangzhou China"},{"name":"The Third Affiliated Hospital Southern Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1070-8021","authenticated-orcid":false,"given":"Xiaokang","family":"Fu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zengping","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nafeisha","family":"Simayi","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongshui","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, School of Biotechnology Southern Medical University  Guangzhou Guangdong China"},{"name":"Guangzhou Blood Center, Institute of Blood Transfusion and Hematology Guangzhou Medical University  Guangzhou Guangdong China"},{"name":"Institute of Blood Transfusion and Hematology Guangzhou First People's Hospital  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaqin","family":"Liang","sequence":"additional","affiliation":[{"name":"Guangzhou Blood Center, Institute of Blood Transfusion and Hematology Guangzhou Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, School of Biotechnology Southern Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhua","family":"Huang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,6]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4086"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.09.001"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.012572"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2940"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.76457"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.11.063"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abe7378"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2020.1847832"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.932412"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2030164"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-200115030-00006"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01245-5"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-00898-z"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41417-023-00593-3"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4441"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0020-8"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021004176"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.07.005"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-04-350686"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.12.019"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.103941"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2010.25"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-019-02385-x"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-023-01614-4"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2016.98"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-023-01602-8"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40115-1"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.958082"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abo4577"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3838"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20230927"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02017-5"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/357161a0"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.01.012"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01726-1"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22070"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djad226"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-024-01207-0"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2008.00745.x"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-00834-9"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-2701"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-005691"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1905675116"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02553-y"},{"issue":"14","key":"e_1_2_10_46_1","first-page":"1632","article-title":"Optimized Tandem CD19\/CD20 CAR\u2010Engineered T Cells in Refractory\/Relapsed B\u2010Cell Lymphoma","volume":"136","author":"Tong C.","year":"2020","journal-title":"Blood"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.08.009"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S297855"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.216043"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.01.006"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-020-00615-4"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12026-021-09236-x"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01702-2"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-065X.2003.00015.x"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0546-z"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-02060-8"}],"updated-by":[{"DOI":"10.1002\/jcp.70039","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T00:00:00Z","timestamp":1744934400000}}],"container-title":["Journal of Cellular Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcp.31520","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T11:32:18Z","timestamp":1748518338000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcp.31520"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1]]},"references-count":55,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["10.1002\/jcp.31520"],"URL":"https:\/\/doi.org\/10.1002\/jcp.31520","archive":["Portico"],"relation":{"correction":[{"id-type":"doi","id":"10.1002\/jcp.70039","asserted-by":"object"}]},"ISSN":["0021-9541","1097-4652"],"issn-type":[{"value":"0021-9541","type":"print"},{"value":"1097-4652","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1]]},"assertion":[{"value":"2024-06-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e31520"}}