FAK在神经系统疾病中的研究进展
Research Progress on FAK in Neurological Diseases
摘要: 黏着斑激酶(FAK)是一种非受体细胞酪氨酸激酶，是主要细胞功能的重要参与者，更是中枢神经系统病理生理过程中一个多功能的核心，它不仅是参与细胞增殖、存活、迁移和侵袭的关键调节器。在感染性与非感染性神经系统疾病中，FAK信号被异常激活，通过调控血脑屏障完整性、神经炎症、胶质细胞反应及神经元存活，发挥着或促进疾病或神经保护的“双面”作用，多项研究已证实FAK在多种人类恶性肿瘤中上调。本文将系统梳理FAK在中枢神经系统疾病背景下被差异调控的机制，重点探讨了其对于疾病发生的作用及作为治疗靶点的潜力，以期为相关领域的研究提供新的理论依据。
Abstract: Focal Adhesion Kinase (FAK) is a non-receptor cell tyrosine kinase that serves as a critical participant in major cellular functions and a multifunctional core in the pathophysiological processes of the Central Nervous System (CNS). It is not only a key regulator involved in cell proliferation, survival, migration, and invasion, but multiple studies have also confirmed the upregulation of FAK in various human malignancies. In both infectious and non-infectious neurological diseases, FAK signaling is abnormally activated, exerting a “dual-faced” role—either promoting disease progression or providing neuroprotection—by regulating Blood-Brain Barrier (BBB) integrity, neuroinflammation, glial cell responses, and neuronal survival. This article systematically reviews the mechanisms underlying the differential regulation of FAK in the context of CNS diseases, with a focus on its role in disease pathogenesis and its potential as a therapeutic target, aiming to provide new theoretical foundations for research in related fields.
文章引用：赵璐, 杨光路. FAK在神经系统疾病中的研究进展 [J]. 临床医学进展, 2026, 16(2): 1990-1999. https://doi.org/10.12677/acm.2026.162595

参考文献

[1] Girault, J.A., Costa, A., Derkinderen, P., Studler, J. and Toutant, M. (1999) FAK and PYK2/CAKbeta in the Nervous System: A Link between Neuronal Activity, Plasticity and Survival? Trends in Neurosciences, 22, 257-263. [Google Scholar] [CrossRef] [PubMed]
[2] Ossovskaya, V., Lim, S., Ota, N., Schlaepfer, D.D. and Ilic, D. (2008) FAK Nuclear Export Signal Sequences. FEBS Letters, 582, 2402-2406. [Google Scholar] [CrossRef] [PubMed]
[3] Zhou, J., Yi, Q. and Tang, L. (2019) The Roles of Nuclear Focal Adhesion Kinase (FAK) on Cancer: A Focused Review. Journal of Experimental & Clinical Cancer Research, 38, Article No. 250. [Google Scholar] [CrossRef] [PubMed]
[4] Cooper, J. and Giancotti, F.G. (2019) Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance. Cancer Cell, 35, 347-367. [Google Scholar] [CrossRef] [PubMed]
[5] Sun, X., Meng, L., Qiao, W., Yang, R., Gao, Q., Peng, Y., et al. (2019) Vascular Endothelial Growth Factor A/Vascular Endothelial Growth Factor Receptor 2 Axis Promotes Human Dental Pulp Stem Cell Migration via the FAK/PI3K/Akt and P38 MAPK Signalling Pathways. International Endodontic Journal, 52, 1691-1703. [Google Scholar] [CrossRef] [PubMed]
[6] Mousson, A., Sick, E., Carl, P., Dujardin, D., De Mey, J. and Rondé, P. (2018) Targeting Focal Adhesion Kinase Using Inhibitors of Protein-Protein Interactions. Cancers, 10, Article No. 278. [Google Scholar] [CrossRef] [PubMed]
[7] Brami-Cherrier, K., Gervasi, N., Arsenieva, D., Walkiewicz, K., Boutterin, M., Ortega, A., et al. (2014) FAK Dimerization Controls Its Kinase-Dependent Functions at Focal Adhesions. The EMBO Journal, 33, 356-370. [Google Scholar] [CrossRef] [PubMed]
[8] Valiente, M., Ciceri, G., Rico, B. and Marín, O. (2011) Focal Adhesion Kinase Modulates Radial Glia-Dependent Neuronal Migration through Connexin-26. The Journal of Neuroscience, 31, 11678-11691. [Google Scholar] [CrossRef] [PubMed]
[9] Davis-Lunn, M., Goult, B.T. and Andrews, M.R. (2023) Clutching at Guidance Cues: The Integrin-FAK Axis Steers Axon Outgrowth. Biology, 12, Article No. 954. [Google Scholar] [CrossRef] [PubMed]
[10] Zhang, J., Li, W., Wang, W., Chen, Q., Xu, Z., Deng, M., et al. (2023) Dual Roles of FAK in Tumor Angiogenesis: A Review Focused on Pericyte Fak. European Journal of Pharmacology, 947, Article ID: 175694. [Google Scholar] [CrossRef] [PubMed]
[11] Zhang, N., Zhu, H., Huang, W., Wen, X., Xie, X., Jiang, X., et al. (2022) Unraveling the Structures, Functions and Mechanisms of Epithelial Membrane Protein Family in Human Cancers. Experimental Hematology & Oncology, 11, Article No. 69. [Google Scholar] [CrossRef] [PubMed]
[12] Tan, X., Yan, Y., Song, B., Zhu, S., Mei, Q. and Wu, K. (2023) Focal Adhesion Kinase: From Biological Functions to Therapeutic Strategies. Experimental Hematology & Oncology, 12, Article No. 83. [Google Scholar] [CrossRef] [PubMed]
[13] Vitillo, L. and Kimber, S.J. (2017) Integrin and FAK Regulation of Human Pluripotent Stem Cells. Current Stem Cell Reports, 3, 358-365. [Google Scholar] [CrossRef] [PubMed]
[14] Yang, M., Xiang, H. and Luo, G. (2024) Targeting Focal Adhesion Kinase (FAK) for Cancer Therapy: FAK Inhibitors, Fak-Based Dual-Target Inhibitors and PROTAC Degraders. Biochemical Pharmacology, 224, Article ID: 116246. [Google Scholar] [CrossRef] [PubMed]
[15] de Pins, B., Mendes, T., Giralt, A. and Girault, J. (2021) The Non-Receptor Tyrosine Kinase Pyk2 in Brain Function and Neurological and Psychiatric Diseases. Frontiers in Synaptic Neuroscience, 13, Article ID: 749001. [Google Scholar] [CrossRef] [PubMed]
[16] Wu, Z., Jiao, M., Shu, C., Zhang, S., Wang, J., Pu, J., et al. (2024) Integrin αVβ1-Activated PYK2 Promotes the Progression of Non-Small-Cell Lung Cancer via the STAT3-VGF Axis. Cell Communication and Signaling, 22, Article No. 313. [Google Scholar] [CrossRef] [PubMed]
[17] Gil-Henn, H., Girault, J. and Lev, S. (2024) PYK2, a Hub of Signaling Networks in Breast Cancer Progression. Trends in Cell Biology, 34, 312-326. [Google Scholar] [CrossRef] [PubMed]
[18] Lim, Y., Lim, S., Tomar, A., Gardel, M., Bernard-Trifilo, J.A., Chen, X.L., et al. (2008) PyK2 and FAK Connections to p190Rho Guanine Nucleotide Exchange Factor Regulate Rhoa Activity, Focal Adhesion Formation, and Cell Motility. The Journal of Cell Biology, 180, 187-203. [Google Scholar] [CrossRef] [PubMed]
[19] Sweeney, M.D., Ayyadurai, S. and Zlokovic, B.V. (2016) Pericytes of the Neurovascular Unit: Key Functions and Signaling Pathways. Nature Neuroscience, 19, 771-783. [Google Scholar] [CrossRef] [PubMed]
[20] Wall, E.C., Chan, J.M., Gil, E. and Heyderman, R.S. (2021) Acute Bacterial Meningitis. Current Opinion in Neurology, 34, 386-395. [Google Scholar] [CrossRef] [PubMed]
[21] Nhu, N.T.K., Phan, M., Hancock, S.J., Peters, K.M., Alvarez-Fraga, L., Forde, B.M., et al. (2024) High-Risk Escherichia coli Clones That Cause Neonatal Meningitis and Association with Recrudescent Infection. eLife, 12, RP91853. [Google Scholar] [CrossRef] [PubMed]
[22] Doran, K.S., Fulde, M., Gratz, N., Kim, B.J., Nau, R., Prasadarao, N., et al. (2016) Host-Pathogen Interactions in Bacterial Meningitis. Acta Neuropathologica, 131, 185-209. [Google Scholar] [CrossRef] [PubMed]
[23] Galea, I. (2021) The Blood-Brain Barrier in Systemic Infection and Inflammation. Cellular & Molecular Immunology, 18, 2489-2501. [Google Scholar] [CrossRef] [PubMed]
[24] Hasbun, R. (2023) Progress and Challenges in Bacterial Meningitis: A Review. JAMA, 329, 515.
[25] Kleinschmidt, E.G. and Schlaepfer, D.D. (2017) Focal Adhesion Kinase Signaling in Unexpected Places. Current Opinion in Cell Biology, 45, 24-30. [Google Scholar] [CrossRef] [PubMed]
[26] Farhadi, P. and Park, T. (2025) The p130Cas-Crk/CrkL Axis: A Therapeutic Target for Invasive Cancers Unveiled by Collaboration among p130Cas, Crk, and CrkL. International Journal of Molecular Sciences, 26, Article No. 4017. [Google Scholar] [CrossRef] [PubMed]
[27] Gil, E., Venturini, C., Stirling, D., Turner, C., Tezera, L.B., Ercoli, G., et al. (2022) Pericyte Derived Chemokines Amplify Neutrophil Recruitment across the Cerebrovascular Endothelial Barrier. Frontiers in Immunology, 13, Article ID: 935798. [Google Scholar] [CrossRef] [PubMed]
[28] Katoh, K. (2024) Signal Transduction Mechanisms of Focal Adhesions: Src and FAK-Mediated Cell Response. Frontiers in Bioscience-Landmark, 29, Article No. 392. [Google Scholar] [CrossRef] [PubMed]
[29] Gerber-Tichet, E., Blanchet, F.P., Majzoub, K. and Kremer, E.J. (2025) Toll-Like Receptor 4—A Multifunctional Virus Recognition Receptor. Trends in Microbiology, 33, 34-47. [Google Scholar] [CrossRef] [PubMed]
[30] Anilkumar, S. and Wright-Jin, E. (2024) NF-κB as an Inducible Regulator of Inflammation in the Central Nervous System. Cells, 13, Article No. 485. [Google Scholar] [CrossRef] [PubMed]
[31] Bivona, G., Iemmolo, M., Agnello, L., Lo Sasso, B., Gambino, C.M., Giglio, R.V., et al. (2023) Microglial Activation and Priming in Alzheimer’s Disease: State of the Art and Future Perspectives. International Journal of Molecular Sciences, 24, Article No. 884. [Google Scholar] [CrossRef] [PubMed]
[32] 许敏慧, 周艺铭, 苏燕, 等. 小胶质细胞脂质代谢在阿尔茨海默病中的作用[J]. 中华神经医学杂志, 2022, 21(11): 1168-1172.
[33] Lewis, J., Dickson, D.W., Lin, W., Chisholm, L., Corral, A., Jones, G., et al. (2001) Enhanced Neurofibrillary Degeneration in Transgenic Mice Expressing Mutant Tau and APP. Science, 293, 1487-1491. [Google Scholar] [CrossRef] [PubMed]
[34] Iijima-Ando, K., Sekiya, M., Maruko-Otake, A., Ohtake, Y., Suzuki, E., Lu, B., et al. (2012) Loss of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration and Alzheimer’s Disease-Related Tau Phosphorylation via PAR-1. PLOS Genetics, 8, e1002918. [Google Scholar] [CrossRef] [PubMed]
[35] Ising, C., Venegas, C., Zhang, S., Scheiblich, H., Schmidt, S.V., Vieira-Saecker, A., et al. (2019) NLRP3 Inflammasome Activation Drives Tau Pathology. Nature, 575, 669-673. [Google Scholar] [CrossRef] [PubMed]
[36] Sekiya, M., Wang, M., Fujisaki, N., Sakakibara, Y., Quan, X., Ehrlich, M.E., et al. (2018) Integrated Biology Approach Reveals Molecular and Pathological Interactions among Alzheimer’s Aβ42, Tau, TREM2, and TYROBP in Drosophila Models. Genome Medicine, 10, Article No. 26. [Google Scholar] [CrossRef] [PubMed]
[37] Lambert, J.C., Ibrahim-Verbaas, C.A., Harold, D., et al. (2013) Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease. Nature Genetics, 45, 1452-1458.
[38] Dourlen, P., Fernandez-Gomez, F.J., Dupont, C., Grenier-Boley, B., Bellenguez, C., Obriot, H., et al. (2016) Functional Screening of Alzheimer Risk Loci Identifies PTK2B as an in Vivo Modulator and Early Marker of Tau Pathology. Molecular Psychiatry, 22, 874-883. [Google Scholar] [CrossRef] [PubMed]
[39] Higa‐Nakamine, S., Okitsu‐Sakurayama, S., Kina, S. and Yamamoto, H. (2020) Fyn‐Mediated Phosphorylation of Pyk2 Promotes Its Activation and Dissociation Downstream of Gonadotropin‐Releasing Hormone Receptor. The FEBS Journal, 287, 3551-3564. [Google Scholar] [CrossRef] [PubMed]
[40] Kaufman, A.C., Salazar, S.V., Haas, L.T., Yang, J., Kostylev, M.A., Jeng, A.T., et al. (2015) Fyn Inhibition Rescues Established Memory and Synapse Loss in Alzheimer Mice. Annals of Neurology, 77, 953-971. [Google Scholar] [CrossRef] [PubMed]
[41] Kumar, R., Tiwari, V. and Dey, S. (2022) Role of Proline‐Rich Tyrosine Kinase 2 (Pyk2) in the Pathogenesis of Alzheimer’s Disease. European Journal of Neuroscience, 56, 5442-5452. [Google Scholar] [CrossRef] [PubMed]
[42] Hardy, J.A. and Higgins, G.A. (1992) Alzheimer’s Disease: The Amyloid Cascade Hypothesis. Science, 256, 184-185. [Google Scholar] [CrossRef] [PubMed]
[43] Wang, X., Chen, Q. and Xing, D. (2012) Focal Adhesion Kinase Activates NF-κB via the ERK1/2 and p38MAPK Pathways in Amyloid-β25-35-Induced Apoptosis in PC12 Cells. Journal of Alzheimer’s Disease, 32, 77-94. [Google Scholar] [CrossRef] [PubMed]
[44] Lee, S., Salazar, S.V., Cox, T.O. and Strittmatter, S.M. (2019) Pyk2 Signaling through Graf1 and RhoA GTPase Is Required for Amyloid-β Oligomer-Triggered Synapse Loss. The Journal of Neuroscience, 39, 1910-1929. [Google Scholar] [CrossRef] [PubMed]
[45] Kilinc, D., Vreulx, A., Mendes, T., Flaig, A., Marques-Coelho, D., Verschoore, M., et al. (2020) Pyk2 Overexpression in Postsynaptic Neurons Blocks Amyloid β1-42-Induced Synaptotoxicity in Microfluidic Co-Cultures. Brain Communications, 2, fcaa139. [Google Scholar] [CrossRef] [PubMed]
[46] Ahmed, S., Kwatra, M., Gawali, B., Panda, S.R. and Naidu, V.G.M. (2020) Potential Role of TrkB Agonist in Neuronal Survival by Promoting CREB/BDNF and PI3K/Akt Signaling in Vitro and in Vivo Model of 3-Nitropropionic Acid (3-NP)-Induced Neuronal Death. Apoptosis, 26, 52-70. [Google Scholar] [CrossRef] [PubMed]
[47] Biswas, K. (2023) Microglia Mediated Neuroinflammation in Neurodegenerative Diseases: A Review on the Cell Signaling Pathways Involved in Microglial Activation. Journal of Neuroimmunology, 383, Article ID: 578180. [Google Scholar] [CrossRef] [PubMed]
[48] Thakur, A., Faujdar, C., Sharma, R., Sharma, S., Malik, B., Nepali, K., et al. (2022) Glioblastoma: Current Status, Emerging Targets, and Recent Advances. Journal of Medicinal Chemistry, 65, 8596-8685. [Google Scholar] [CrossRef] [PubMed]
[49] Pouyan, A., Ghorbanlo, M., Eslami, M., Jahanshahi, M., Ziaei, E., Salami, A., et al. (2025) Glioblastoma Multiforme: Insights into Pathogenesis, Key Signaling Pathways, and Therapeutic Strategies. Molecular Cancer, 24, Article No. 58. [Google Scholar] [CrossRef] [PubMed]
[50] Li, B., Li, Y., Tomkiewicz-Raulet, C., Dao, P., Lietha, D., Yen-Pon, E., et al. (2020) Design, Synthesis, and Biological Evaluation of Covalent Inhibitors of Focal Adhesion Kinase (FAK) against Human Malignant Glioblastoma. Journal of Medicinal Chemistry, 63, 12707-12724. [Google Scholar] [CrossRef] [PubMed]
[51] Brown, N.F., Williams, M., Arkenau, H., Fleming, R.A., Tolson, J., Yan, L., et al. (2018) A Study of the Focal Adhesion Kinase Inhibitor GSK2256098 in Patients with Recurrent Glioblastoma with Evaluation of Tumor Penetration of [11C]GSK2256098. Neuro-Oncology, 20, 1634-1642. [Google Scholar] [CrossRef] [PubMed]
[52] Sharma, R. and Lee, K. (2025) Advances in Treatments for Acute Ischemic Stroke. BMJ, 389, e076161. [Google Scholar] [CrossRef] [PubMed]
[53] Brastianos, P.K., Twohy, E.L., Gerstner, E.R., et al. (2023) Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas with Somatic NF2 Mutations. Journal of Clinical Oncology, 41, 618-628.
[54] Zhang, Y.W., Hu, Y.X., Chu, L.Z., et al. (2023) Knockdown of CREB3 Inhibits Proliferation, Migration, and Invasion of Glioma Cells by Decreasing Phosphorylated FAK (Tyr397) Expression. Chinese Journal of Clinicians (Electronic Edition), 17, 202-209.
[55] Lyden, P., Buchan, A., Boltze, J., Fisher, M., Ansari, S., Broderick, J.P., et al. (2021) Top Priorities for Cerebroprotective Studies—A Paradigm Shift: Report from STAIR XI. Stroke, 52, 3063-3071. [Google Scholar] [CrossRef] [PubMed]
[56] Jia, C., Keasey, M.P., Malone, H.M., Lovins, C. and Hagg, T. (2020) Vitronectin Mitigates Stroke-Increased Neurogenesis Only in Female Mice and through FAK-Regulated IL-6. Experimental Neurology, 323, Article ID: 113088. [Google Scholar] [CrossRef] [PubMed]
[57] Erta, M., Giralt, M., Jiménez, S., Molinero, A., Comes, G. and Hidalgo, J. (2016) Astrocytic IL-6 Influences the Clinical Symptoms of EAE in Mice. Brain Sciences, 6, Article No. 15. [Google Scholar] [CrossRef] [PubMed]
[58] Takada, Y., Ye, X. and Simon, S. (2007) The Integrins. Genome Biology, 8, Article No. 215. [Google Scholar] [CrossRef] [PubMed]
[59] Kerr, N., Dietrich, D.W., Bramlett, H.M. and Raval, A.P. (2019) Sexually Dimorphic Microglia and Ischemic Stroke. CNS Neuroscience & Therapeutics, 25, 1308-1317. [Google Scholar] [CrossRef] [PubMed]
[60] Zhao, R., Zhou, X., Zhao, Z., Liu, W., Lv, M., Zhang, Z., et al. (2024) Farrerol Alleviates Cerebral Ischemia-Reperfusion Injury by Promoting Neuronal Survival and Reducing Neuroinflammation. Molecular Neurobiology, 61, 7239-7255. [Google Scholar] [CrossRef] [PubMed]
[61] Jia, C., Lovins, C., Malone, H.M., Keasey, M.P. and Hagg, T. (2022) Female-Specific Neuroprotection after Ischemic Stroke by Vitronectin-Focal Adhesion Kinase Inhibition. Journal of Cerebral Blood Flow & Metabolism, 42, 1961-1974. [Google Scholar] [CrossRef] [PubMed]
[62] Golubovskaya, V.M., Nyberg, C., Zheng, M., Kweh, F., Magis, A., Ostrov, D., et al. (2008) A Small Molecule Inhibitor, 1,2,4,5-Benzenetetraamine Tetrahydrochloride, Targeting the Y397 Site of Focal Adhesion Kinase Decreases Tumor Growth. Journal of Medicinal Chemistry, 51, 7405-7416. [Google Scholar] [CrossRef] [PubMed]
[63] Dong, B., Chang, M., Liu, J., Li, K., Xiao, H., Wu, S., et al. (2025) Changes in Peripheral Immune Cell Phenotypes and Their Roles in Autism: Insights from Clinical and Animal Model Studies. Molecular Psychiatry, 31, 1111-1120. [Google Scholar] [CrossRef] 
[64] Xiang, H., Zhang, J., Lin, C., Zhang, L., Liu, B. and Ouyang, L. (2020) Targeting Autophagy-Related Protein Kinases for Potential Therapeutic Purpose. Acta Pharmaceutica Sinica B, 10, 569-581. [Google Scholar] [CrossRef] [PubMed]
[65] Reich, D.S., Arnold, D.L., Vermersch, P., et al. (2021) Safety and Efficacy of Tolebrutinib, an Oral Brain-Penetrant BTK Inhibitor, in Relapsing Multiple Sclerosis: A Phase 2b, Randomised, Double-Blind, Placebo-Controlled Trial. The Lancet Neurology, 20, 729-738.

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