PAK激酶调节Rac GTP酶，是人类神经鞘瘤的一个潜在靶点。
PAK kinase regulates Rac GTPase and is a potential target in human schwannomas.
作者信息
Flaiz Christine, Chernoff Jonathan, Ammoun Sylwia, Peterson Jeffrey R, Hanemann Clemens O
机构信息
Clinical Neurobiology, Peninsula College for Medicine and Dentistry, The John Bull Building, Tamar Science Park, Research Way, Plymouth PL6 8BU, UK.
出版信息
Exp Neurol. 2009 Jul;218(1):137-44. doi: 10.1016/j.expneurol.2009.04.019. Epub 2009 May 3.
Abstract
Merlin loss causes benign tumours of the nervous system, mainly schwannomas and meningiomas. Schwannomas show enhanced Rac1 and Cdc42 activity, the p21-activated kinase 2 (PAK2) activation and increased ruffling and cell adhesion. PAK regulates activation of merlin. PAK has been proposed as a potential therapeutic target in schwannomas. However where PAK stands in the Rac pathway is insufficiently characterised. We used a novel small-molecule PAK inhibitor, IPA-3, to investigate the role of PAK activation on Rac1/Cdc42 activity, cell spreading and adhesion in human primary schwannoma and Schwann cells. We show that IPA-3 blocks activation of PAK2 at Ser192/197 that antagonises PAK's interaction with Pix. Accordingly, Pix-mediated Rac1 activation is decreased in IPA-3 treated schwannoma cells, indicating that PAK acts upstream of Rac. We show that this Rac activation at the level of focal adhesions in schwannoma cells is essential for cell spreading and adhesion in Schwann and schwannoma cells.
摘要
Merlin缺失会导致神经系统的良性肿瘤，主要是神经鞘瘤和脑膜瘤。神经鞘瘤表现出Rac1和Cdc42活性增强、p21激活激酶2（PAK2）激活以及褶皱和细胞黏附增加。PAK调节Merlin的激活。PAK已被提议作为神经鞘瘤的潜在治疗靶点。然而，PAK在Rac信号通路中的位置尚未得到充分表征。我们使用一种新型小分子PAK抑制剂IPA-3，来研究PAK激活对人原发性神经鞘瘤和雪旺细胞中Rac1/Cdc42活性、细胞铺展和黏附的作用。我们发现IPA-3可阻断PAK2在Ser192/197位点的激活，这会拮抗PAK与Pix的相互作用。相应地，在经IPA-3处理的神经鞘瘤细胞中，Pix介导的Rac1激活减少，表明PAK在Rac上游发挥作用。我们表明，神经鞘瘤细胞中黏着斑水平的这种Rac激活对于雪旺细胞和神经鞘瘤细胞的铺展和黏附至关重要。
相似文献
1
PAK kinase regulates Rac GTPase and is a potential target in human schwannomas.PAK激酶调节Rac GTP酶，是人类神经鞘瘤的一个潜在靶点。
Exp Neurol. 2009 Jul;218(1):137-44. doi: 10.1016/j.expneurol.2009.04.019. Epub 2009 May 3.
2
Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane.默林蛋白/神经纤维瘤病2型（Merlin/NF-2）通过抑制Rac蛋白募集至质膜来介导生长接触抑制。
J Cell Biol. 2005 Oct 24;171(2):361-71. doi: 10.1083/jcb.200503165.
3
FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas.FRAX597 是一种 p21 激活激酶的小分子抑制剂，可抑制神经纤维瘤病 2 型（NF2）相关神经鞘瘤的肿瘤发生。
J Biol Chem. 2013 Oct 4;288(40):29105-14. doi: 10.1074/jbc.M113.510933. Epub 2013 Aug 19.
4
Paxillin-dependent paxillin kinase linker and p21-activated kinase localization to focal adhesions involves a multistep activation pathway.桩蛋白依赖性桩蛋白激酶连接蛋白和p21激活激酶定位于粘着斑涉及一个多步骤激活途径。
Mol Biol Cell. 2002 May;13(5):1550-65. doi: 10.1091/mbc.02-02-0015.
5
A RAC/CDC-42-independent GIT/PIX/PAK signaling pathway mediates cell migration in C. elegans.一条不依赖RAC/CDC-42的GIT/PIX/PAK信号通路介导秀丽隐杆线虫中的细胞迁移。
PLoS Genet. 2008 Nov;4(11):e1000269. doi: 10.1371/journal.pgen.1000269. Epub 2008 Nov 21.
6
Activation of cdc42, rac, PAK, and rho-kinase in response to hepatocyte growth factor differentially regulates epithelial cell colony spreading and dissociation.响应肝细胞生长因子时，细胞分裂周期蛋白42（cdc42）、Rac蛋白、p21激活激酶（PAK）和 Rho激酶的激活对上皮细胞集落的扩散和解离具有不同的调节作用。
Mol Biol Cell. 2000 May;11(5):1709-25. doi: 10.1091/mbc.11.5.1709.
7
Merlin-deficient human tumors show loss of contact inhibition and activation of Wnt/β-catenin signaling linked to the PDGFR/Src and Rac/PAK pathways.梅林缺陷型人类肿瘤表现出接触抑制丧失，并激活与 PDGFR/Src 和 Rac/PAK 通路相关的 Wnt/β-catenin 信号传导。
Neoplasia. 2011 Dec;13(12):1101-12. doi: 10.1593/neo.111060.
8
Impaired intercellular adhesion and immature adherens junctions in merlin-deficient human primary schwannoma cells.默林蛋白缺陷的人原发性施万细胞瘤细胞中细胞间黏附受损及黏着连接不成熟。
Glia. 2008 Apr;56(5):506-15. doi: 10.1002/glia.20629.
9
Upregulation of the Rac1/JNK signaling pathway in primary human schwannoma cells.原代人雪旺氏细胞瘤细胞中Rac1/JNK信号通路的上调
Hum Mol Genet. 2003 Jun 1;12(11):1211-21. doi: 10.1093/hmg/ddg146.
10
Altered adhesive structures and their relation to RhoGTPase activation in merlin-deficient Schwannoma.在缺乏默林的施万细胞瘤中，黏附结构的改变及其与RhoGTP酶激活的关系。
Brain Pathol. 2009 Jan;19(1):27-38. doi: 10.1111/j.1750-3639.2008.00165.x. Epub 2008 Apr 25.
引用本文的文献
1
Regulation of Vascular Injury and Repair by P21-Activated Kinase 1 and P21-Activated Kinase 2: Therapeutic Potential and Challenges.p21激活激酶1和p21激活激酶2对血管损伤与修复的调控：治疗潜力与挑战
Biomolecules. 2024 Dec 13;14(12):1596. doi: 10.3390/biom14121596.
2
Rac1 GTPase Regulates the βTrCP-Mediated Proteolysis of YAP Independently of the LATS1/2 Kinases.Rac1 GTP酶独立于LATS1/2激酶调节βTrCP介导的YAP蛋白水解。
Cancers (Basel). 2024 Oct 25;16(21):3605. doi: 10.3390/cancers16213605.
3
Targeting the Hippo pathway in Schwann cells ameliorates peripheral nerve degeneration via a polypharmacological mechanism.靶向施万细胞中的 Hippo 通路通过多药理学机制改善周围神经变性。
Neurotherapeutics. 2024 Oct;21(6):e00458. doi: 10.1016/j.neurot.2024.e00458. Epub 2024 Oct 8.
4
Genetic mutation and immune infiltration in embryonal tumor with multilayered rosettes.具有多层菊形团的胚胎性肿瘤中的基因突变和免疫浸润。
Childs Nerv Syst. 2024 Sep;40(9):2685-2696. doi: 10.1007/s00381-024-06461-1. Epub 2024 May 28.
5
Updates on Tumor Biology in Vestibular Schwannoma.前庭神经鞘瘤的肿瘤生物学研究进展。
Otolaryngol Clin North Am. 2023 Jun;56(3):421-434. doi: 10.1016/j.otc.2023.02.004.
6
Potential Molecular Biomarkers of Vestibular Schwannoma Growth: Progress and Prospects.前庭神经鞘瘤生长的潜在分子生物标志物：进展与展望
Front Oncol. 2021 Sep 27;11:731441. doi: 10.3389/fonc.2021.731441. eCollection 2021.
7
The biological underpinnings of radiation therapy for vestibular schwannomas: Review of the literature.前庭神经鞘瘤放射治疗的生物学基础：文献综述
Laryngoscope Investig Otolaryngol. 2021 Mar 30;6(3):458-468. doi: 10.1002/lio2.553. eCollection 2021 Jun.
8
Effect of P21-activated kinase 1 (PAK-1) inhibition on cancer cell growth, migration, and invasion.P21 激活激酶 1（PAK-1）抑制对癌细胞生长、迁移和侵袭的影响。
Pharmacol Res Perspect. 2019 Sep 6;7(5):e00518. doi: 10.1002/prp2.518. eCollection 2019 Oct.
9
Persistent Oxidative Stress in Vestibular Schwannomas After Stereotactic Radiation Therapy.前庭神经鞘瘤立体定向放射治疗后持续氧化应激。
Otol Neurotol. 2018 Oct;39(9):1184-1190. doi: 10.1097/MAO.0000000000001935.
10
p21-activated kinase 2 regulates HSPC cytoskeleton, migration, and homing via CDC42 activation and interaction with β-Pix.p21激活激酶2通过激活CDC42并与β-Pix相互作用来调节造血干细胞的细胞骨架、迁移和归巢。
Blood. 2016 Apr 21;127(16):1967-75. doi: 10.1182/blood-2016-01-693572. Epub 2016 Mar 1.
本文引用的文献
1
Dissecting and targeting the growth factor-dependent and growth factor-independent extracellular signal-regulated kinase pathway in human schwannoma.剖析并靶向人类神经鞘瘤中依赖生长因子和不依赖生长因子的细胞外信号调节激酶通路
Cancer Res. 2008 Jul 1;68(13):5236-45. doi: 10.1158/0008-5472.CAN-07-5849.
2
Altered adhesive structures and their relation to RhoGTPase activation in merlin-deficient Schwannoma.在缺乏默林的施万细胞瘤中，黏附结构的改变及其与RhoGTP酶激活的关系。
Brain Pathol. 2009 Jan;19(1):27-38. doi: 10.1111/j.1750-3639.2008.00165.x. Epub 2008 Apr 25.
3
An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase.一种亚型选择性小分子抑制剂靶向p21活化激酶的自动调节机制。
Chem Biol. 2008 Apr;15(4):322-31. doi: 10.1016/j.chembiol.2008.03.005.
4
Hormesis: why it is important to toxicology and toxicologists.毒物兴奋效应：为何它对毒理学及毒理学家至关重要。
Environ Toxicol Chem. 2008 Jul;27(7):1451-74. doi: 10.1897/07-541.
5
Impaired intercellular adhesion and immature adherens junctions in merlin-deficient human primary schwannoma cells.默林蛋白缺陷的人原发性施万细胞瘤细胞中细胞间黏附受损及黏着连接不成熟。
Glia. 2008 Apr;56(5):506-15. doi: 10.1002/glia.20629.
6
Neuregulin and laminin stimulate phosphorylation of the NF2 tumor suppressor in Schwann cells by distinct protein kinase A and p21-activated kinase-dependent pathways.神经调节蛋白和层粘连蛋白通过不同的蛋白激酶A和p21激活激酶依赖性途径刺激雪旺细胞中NF2肿瘤抑制因子的磷酸化。
Oncogene. 2008 Apr 24;27(19):2705-15. doi: 10.1038/sj.onc.1210923. Epub 2007 Nov 12.
7
Actin-rich protrusions and nonlocalized GTPase activation in Merlin-deficient schwannomas.在缺乏Merlin的神经鞘瘤中富含肌动蛋白的突起和非局部性GTP酶激活。
J Neuropathol Exp Neurol. 2007 Jul;66(7):608-16. doi: 10.1097/nen.0b013e318093e555.
8
Beta1 integrin activates Rac1 in Schwann cells to generate radial lamellae during axonal sorting and myelination.β1整合素激活雪旺细胞中的Rac1，在轴突分选和髓鞘形成过程中产生放射状薄片。
J Cell Biol. 2007 Jun 18;177(6):1063-75. doi: 10.1083/jcb.200610014.
9
Essential and distinct roles for cdc42 and rac1 in the regulation of Schwann cell biology during peripheral nervous system development.在周围神经系统发育过程中，Cdc42和Rac1在雪旺细胞生物学调控中具有重要且独特的作用。
J Cell Biol. 2007 Jun 18;177(6):1051-61. doi: 10.1083/jcb.200610108.
10
Phosphorylation of the NF2 tumor suppressor in Schwann cells is mediated by Cdc42-Pak and requires paxillin binding.雪旺细胞中NF2肿瘤抑制因子的磷酸化由Cdc42-Pak介导，且需要桩蛋白结合。
Mol Cell Neurosci. 2007 Feb;34(2):231-42. doi: 10.1016/j.mcn.2006.11.003. Epub 2006 Dec 18.
Zotero 插件