Generic placeholder image

Current Enzyme Inhibition


ISSN (Print): 1573-4080
ISSN (Online): 1875-6662

Research Article

Interactions of Butyrylcholinesterase with Neuroblastoma-associated Oncoproteins

Author(s): Janina Baranowska-Kortylewicz*, Zbigniew P. Kortylewicz, Erin M. McIntyre, John G. Sharp and Don W. Coulter

Volume 19, Issue 2, 2023

Published on: 20 March, 2023

Page: [109 - 124] Pages: 16

DOI: 10.2174/1573408019666230206151403

Price: $65


Background: Emerging data indicate that BCHE, a gene encoding the enzyme butyrylcholinesterase, is a negative prognostic marker in MYCN-amplified neuroblastoma. Levels of butyrylcholinesterase in children newly diagnosed with neuroblastoma are proportional to MYCN amplification and the response to therapy. To better understand the functions of butyrylcholinesterase in neuroblastoma, we examine interactions of this enzyme with several neuroblastoma-associated kinases and provide in depth review of known associations.

Methods: BCHE-deleted cells (KO) were produced from MYCN-amplified BE(2)-C cells (WT) by the CRISPR-Cas9 targeted disruption of the BCHE locus. Activation levels of several oncoproteins and the expression of N-Myc in KO were compared to WT cells. N-Myc protein expression, multiplexed detection of relative protein expression and phosphorylation of 71 tyrosine kinases and 17 proteins in the MAPK pathway were assessed using Western immunoblotting and microarrays in exponentially growing untreated cells and in cells exposed to the genotoxic stress.

Results: BCHE locus disruption and butyrylcholinesterase deficiency result in the loss of N-Myc protein and a significant deactivation of several kinases associated with the aggressive neuroblastoma phenotype as well as major changes in the phosphorylation of upstream and downstream partners of these kinases.

Conclusion: Butyrylcholinesterase appears to contribute to the activation of several pathways in MYCN-amplified cells including FGF-R1, Ltk, TrkB, and Ros1. Deletion of BCHE and ensuing butyrylcholinesterase deficit deactivate these pathways suggesting the role of BChE as a novel druggable target in neuroblastoma therapy.

Keywords: Butyrylcholinesterase, neuroblastoma, BCHE locus disruption, oncoproteins, N-Myc, Ltk, FGF-R1, Ros1, TrkB.

Graphical Abstract
Willbold E, Layer PG. Butyrylcholinesterase regulates laminar retinogenesis of the chick embryo in vitro. Eur J Cell Biol 1994; 64(1): 192-9.
[PMID: 7957307]
Baranowska-Kortylewicz J, Kortylewicz ZP, McIntyre EM, Sharp JG, Coulter DW. Multifarious functions of butyrylcholinesterase in neuroblastoma: Impact of BCHE deletion on the neuroblastoma growth in vitro and in vivo. J Pediatr Hematol Oncol 2021.
[] [PMID: 34486544]
Robitzki A, Mack A, Chatonnet A, Layer PG. Transfection of reaggregating embryonic chicken retinal cells with an antisense 5′-DNA butyrylcholinesterase expression vector inhibits proliferation and alters morphogenesis. J Neurochem 1997; 69(2): 823-33.
[] [PMID: 9231744]
Robitzki A, Mack A, Hoppe U, Chatonnet A, Layer PG. Regulation of cholinesterase gene expression affects neuronal differentiation as revealed by transfection studies on reaggregating embryonic chicken retinal cells. Eur J Neurosci 1997; 9(11): 2394-405.
[] [PMID: 9464933]
Small DH, Michaelson S, Sberna G. Non-classical actions of cholinesterases: Role in cellular differentiation, tumorigenesis and Alzheimer’s disease. Neurochem Int 1996; 28(5-6): 453-83.
[] [PMID: 8792327]
Mack A, Robitzki A. The key role of butyrylcholinesterase during neurogenesis and neural disorders: An antisense-5′butyrylcholinesterase-DNA study. Prog Neurobiol 2000; 60(6): 607-28.
[] [PMID: 10739090]
Bodur E, Layer PG. Counter-regulation of cholinesterases: Differential activation of PKC and ERK signaling in retinal cells through BChE knockdown. Biochimie 2011; 93(3): 469-76.
[] [PMID: 21094673]
Darreh-Shori T, Vijayaraghavan S, Aeinehband S, et al. Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer’s disease. Neurobiol Aging 2013; 34(11): 2465-81.
[] [PMID: 23759148]
Zakut H, Ehrlich G, Ayalon A, et al. Acetylcholinesterase and butyrylcholinesterase genes coamplify in primary ovarian carcinomas. J Clin Invest 1990; 86(3): 900-8.
[] [PMID: 2394839]
Brass N, Rácz A, Heckel D, Remberger K, Sybrecht GW, Meese EU. Amplification of the genes BCHE and SLC2A2 in 40% of squamous cell carcinoma of the lung. Cancer Res 1997; 57(11): 2290-4.
[PMID: 9187134]
Bernardi CC, Ribeiro Ede S, Cavalli IJ, Chautard-Freire-Maia EA, Souza RL. Amplification and deletion of the ACHE and BCHE cholinesterase genes in sporadic breast cancer. Cancer Genet Cytogenet 2010; 197(2): 158-65.
Coulter DW, Boettner AD, Kortylewicz ZP, et al. Butyrylcholinesterase as a blood biomarker in neuroblastoma. J Pediatr Hematol Oncol 2017; 39(4): 272-81.
[] [PMID: 28375942]
Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 1984; 224(4653): 1121-4.
[] [PMID: 6719137]
Schwab M, Alitalo K, Klempnauer KH, et al. Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature 1983; 305(5931): 245-8.
[] [PMID: 6888561]
Kohl NE, Kanda N, Schreck RR, et al. Transposition and amplification of oncogene-related sequences in human neuroblastomas. Cell 1983; 35(2): 359-67.
[] [PMID: 6197179]
Chan HS, Gallie BL, DeBoer G, et al. MYCN protein expression as a predictor of neuroblastoma prognosis. Clin Cancer Res 1997; 3(10): 1699-706.
[PMID: 9815553]
Nara K, Kusafuka T, Yoneda A, Oue T, Sangkhathat S, Fukuzawa M. Silencing of MYCN by RNA interference induces growth inhibition, apoptotic activity and cell differentiation in a neuroblastoma cell line with MYCN amplification. Int J Oncol 2007; 30(5): 1189-96.
[] [PMID: 17390021]
George RE, Variend S, Cullinane C, et al. Relationship between histopathological features, MYCN amplification, and prognosis: A UKCCSG study. Med Pediatr Oncol 2001; 36(1): 169-76.
[<169:AID-MPO1041>3.0.CO;2-U] [PMID: 11464876]
Wakamatsu Y, Watanabe Y, Nakamura H, Kondoh H. Regulation of the neural crest cell fate by N-myc: Promotion of ventral migration and neuronal differentiation. Development 1997; 124(10): 1953-62.
[] [PMID: 9169842]
Kang JH, Rychahou PG, Ishola TA, Qiao J, Evers BM, Chung DH. MYCN silencing induces differentiation and apoptosis in human neuroblastoma cells. Biochem Biophys Res Commun 2006; 351(1): 192-7.
[] [PMID: 17055458]
Henriksen JR, Haug BH, Buechner J, et al. Conditional expression of retrovirally delivered anti-MYCN shRNA as an in vitro model system to study neuronal differentiation in MYCN-amplified neuroblastoma. BMC Dev Biol 2011; 11(1): 1.
[] [PMID: 21194500]
Seeger RC, Brodeur GM, Sather H, et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 1985; 313(18): 1111-6.
[] [PMID: 4047115]
Varlakhanova NV, Cotterman RF, deVries WN, et al. myc maintains embryonic stem cell pluripotency and self-renewal. Differentiation 2010; 80(1): 9-19.
[] [PMID: 20537458]
Westermark UK, Wilhelm M, Frenzel A, Henriksson MA. The MYCN oncogene and differentiation in neuroblastoma. Semin Cancer Biol 2011; 21(4): 256-66.
[] [PMID: 21849159]
Hasan MK, Nafady A, Takatori A, et al. ALK is a MYCN target gene and regulates cell migration and invasion in neuroblastoma. Sci Rep 2013; 3(1): 3450.
[] [PMID: 24356251]
Haninec P, Dubový P. Origin of cells in contact with the growth cones of embryonal peripheral nerves and histochemical detection of nonspecific cholinesterase activity in quail-chick and chick-quail chimeras. J Neurosci Res 1992; 31(2): 301-8.
[] [PMID: 1573680]
Layer PG. Nonclassical roles of cholinesterases in the embryonic brain and possible links to Alzheimer disease. Alzheimer Dis Assoc Disord 1995; 9 (Suppl. 2): 29-36.
[] [PMID: 8534420]
Lee JW, Park SH, Kang HJ, Park KD, Shin HY, Ahn HS. ALK protein expression is related to neuroblastoma aggressiveness but is not independent prognostic factor. Cancer Res Treat 2018; 50(2): 495-505.
[] [PMID: 28546523]
Kramer M, Ribeiro D, Arsenian-Henriksson M, Deller T, Rohrer H. Proliferation and survival of embryonic sympathetic neuroblasts by MYCN and activated ALK signaling. J Neurosci 2016; 36(40): 10425-39.
[] [PMID: 27707976]
Zeid R, Lawlor MA, Poon E, et al. Enhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma. Nat Genet 2018; 50(4): 515-23.
[] [PMID: 29379199]
Cazes A, Lopez-Delisle L, Tsarovina K, et al. Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma. Oncotarget 2014; 5(9): 2688-702.
[] [PMID: 24811913]
Enomoto H, Crawford PA, Gorodinsky A, Heuckeroth RO, Johnson EM Jr, Milbrandt J. RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons. Development 2001; 128(20): 3963-74.
[] [PMID: 11641220]
Cerchia L, D’Alessio A, Amabile G, et al. An autocrine loop involving ret and glial cell-derived neurotrophic factor mediates retinoic acid-induced neuroblastoma cell differentiation. Mol Cancer Res 2006; 4(7): 481-8.
[] [PMID: 16849523]
Oppenheimer O, Cheung NK, Gerald WL. The RET oncogene is a critical component of transcriptional programs associated with retinoic acid–induced differentiation in neuroblastoma. Mol Cancer Ther 2007; 6(4): 1300-9.
[] [PMID: 17431108]
Bunone G, Borrello MG, Picetti R, et al. Induction of RET proto-oncogene expression in neuroblastoma cells precedes neuronal differentiation and is not mediated by protein synthesis. Exp Cell Res 1995; 217(1): 92-9.
[] [PMID: 7867726]
Esposito CL, D’Alessio A, de Franciscis V, Cerchia L. A cross-talk between TrkB and Ret tyrosine kinases receptors mediates neuroblastoma cells differentiation. PLoS One 2008; 3(2): e1643.
[] [PMID: 18286198]
Aygun N. Biological and genetic features of neuroblastoma and their clinical importance. Curr Pediatr Rev 2018; 14(2): 73-90.
[] [PMID: 29380702]
Nakagawara A, Azar CG, Scavarda NJ, Brodeur GM. Expression and function of TRK-B and BDNF in human neuroblastomas. Mol Cell Biol 1994; 14(1): 759-67.
[] [PMID: 8264643]
Edsjö A, Lavenius E, Nilsson H, et al. Expression of trkB in human neuroblastoma in relation to MYCN expression and retinoic acid treatment. Lab Invest 2003; 83(6): 813-23.
[] [PMID: 12808116]
Jaboin J, Kim CJ, Kaplan DR, Thiele CJ. Brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from chemotherapy-induced apoptosis via phosphatidylinositol 3′-kinase pathway. Cancer Res 2002; 62(22): 6756-63.
[PMID: 12438277]
Schramm A, Schulte JH, Astrahantseff K, et al. Biological effects of TrkA and TrkB receptor signaling in neuroblastoma. Cancer Lett 2005; 228(1-2): 143-53.
[] [PMID: 15921851]
Matsumoto K, Wada RK, Yamashiro JM, Kaplan DR, Thiele CJ. Expression of brain-derived neurotrophic factor and p145TrkB affects survival, differentiation, and invasiveness of human neuroblastoma cells. Cancer Res 1995; 55(8): 1798-806.
[PMID: 7712490]
Cimmino F, Schulte JH, Zollo M, et al. Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness. Oncogene 2009; 28(19): 2015-23.
[] [PMID: 19363525]
Li Z, Jaboin J, Dennis PA, Thiele CJ. Genetic and pharmacologic identification of Akt as a mediator of brain-derived neurotrophic factor/TrkB rescue of neuroblastoma cells from chemotherapy-induced cell death. Cancer Res 2005; 65(6): 2070-5.
[] [PMID: 15781614]
Opel D, Poremba C, Simon T, Debatin KM, Fulda S. Activation of Akt predicts poor outcome in neuroblastoma. Cancer Res 2007; 67(2): 735-45.
[] [PMID: 17234785]
Iżycka-Świeszewska E, Drożyńska E, Rzepko R, et al. Analysis of PI3K/AKT/mTOR signalling pathway in high risk neuroblastic tumours. Pol J Pathol 2010; 61(4): 192-8.
[PMID: 21290341]
Qi L, Toyoda H, Shankar V, et al. Heterogeneity of neuroblastoma cell lines in insulin-like growth factor 1 receptor/Akt pathway-mediated cell proliferative responses. Cancer Sci 2013; 104(9): 1162-71.
[] [PMID: 23710710]
Huang M, Weiss WA. Neuroblastoma and MYCN. Cold Spring Harb Perspect Med 2013; 3(10): a014415.
[] [PMID: 24086065]
Beltran H. The N-myc oncogene: Maximizing its targets, regulation, and therapeutic potential. Mol Cancer Res 2014; 12(6): 815-22.
[] [PMID: 24589438]
Matthay KK, Maris JM, Schleiermacher G, et al. Neuroblastoma. Nat Rev Dis Primers 2016; 2(1): 16078.
[] [PMID: 27830764]
Negroni A, Scarpa S, Romeo A, Ferrari S, Modesti A, Raschellà G. Decrease of proliferation rate and induction of differentiation by a MYCN antisense DNA oligomer in a human neuroblastoma cell line. Cell Growth Differ 1991; 2(10): 511-8.
[PMID: 1751406]
Johnsen JI, Segerström L, Orrego A, et al. Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo. Oncogene 2008; 27(20): 2910-22.
[] [PMID: 18026138]
Le Grand M, Mukha A, Püschel J, et al. Interplay between MycN and c-Myc regulates radioresistance and cancer stem cell phenotype in neuroblastoma upon glutamine deprivation. Theranostics 2020; 10(14): 6411-29.
[] [PMID: 32483461]
Livingstone A, Mairs RJ, Russell J, O’Donoghue J, Gaze MN, Wheldon TE. N-myc gene copy number in neuroblastoma cell lines and resistance to experimental treatment. Eur J Cancer 1994; 30(3): 382-9.
[] [PMID: 8204363]
Rached J, Nasr Z, Abdallah J, Abou-Antoun T. L1-CAM knock-down radiosensitizes neuroblastoma IMR-32 cells by simultaneously decreasing MycN, but increasing PTEN protein expression. Int J Oncol 2016; 49(4): 1722-30.
[] [PMID: 27432152]
Watanabe N, Sawai H, Ogihara-Umeda I, et al. Molecular therapy of human neuroblastoma cells using Auger electrons of 111In-labeled N-myc antisense oligonucleotides. J Nucl Med 2006; 47(10): 1670-7.
[PMID: 17015904]
Lee ACL, Shih YY, Zhou F, et al. Calreticulin regulates MYCN expression to control neuronal differentiation and stemness of neuroblastoma. J Mol Med 2019; 97(3): 325-39.
[] [PMID: 30612140]
Roll JD, Reuther GW. ALK-activating homologous mutations in LTK induce cellular transformation. PLoS One 2012; 7(2): e31733.
[] [PMID: 22347506]
Yamada S, Nomura T, Takano K, Fujita S, Miyake M, Miyake J. Expression of a chimeric CSF1R-LTK mediates ligand-dependent neurite outgrowth. Neuroreport 2008; 19(17): 1733-8.
[] [PMID: 18849880]
Weiss JB, Xue C, Benice T, Xue L, Morris SW, Raber J. Anaplastic lymphoma kinase and leukocyte tyrosine kinase: Functions and genetic interactions in learning, memory and adult neurogenesis. Pharmacol Biochem Behav 2012; 100(3): 566-74.
[] [PMID: 22079349]
Vieceli FM, Bronner ME. Leukocyte receptor tyrosine kinase interacts with secreted midkine to promote survival of migrating neural crest cells. Development 2018; 145(20): dev.164046.
[] [PMID: 30228102]
Futami H, Sakai R. RET protein promotes non-adherent growth of NB-39-nu neuroblastoma cell line. Cancer Sci 2009; 100(6): 1034-9.
[] [PMID: 19320641]
Lopez-Delisle L, Pierre-Eugène C, Louis-Brennetot C, et al. Activated ALK signals through the ERK–ETV5–RET pathway to drive neuroblastoma oncogenesis. Oncogene 2018; 37(11): 1417-29.
[] [PMID: 29321660]
Layer PG. Comparative localization of acetylcholinesterase and pseudocholinesterase during morphogenesis of the chicken brain. Proc Natl Acad Sci 1983; 80(20): 6413-7.
[] [PMID: 6578516]
Layer PG, Sporns O. Spatiotemporal relationship of embryonic cholinesterases with cell proliferation in chicken brain and eye. Proc Natl Acad Sci 1987; 84(1): 284-8.
[] [PMID: 3467355]
DeNardo BD, Holloway MP, Ji Q, et al. Quantitative phosphoproteomic analysis identifies activation of the RET and IGF-1R/IR signaling pathways in neuroblastoma. PLoS One 2013; 8(12): e82513.
[] [PMID: 24349301]
DiCicco-Bloom E, Black IB. Insulin growth factors regulate the mitotic cycle in cultured rat sympathetic neuroblasts. Proc Natl Acad Sci 1988; 85(11): 4066-70.
[] [PMID: 2897692]
Coulter DW, Blatt J, D’Ercole AJ, Moats-Staats BM. IGF-I receptor inhibition combined with rapamycin or temsirolimus inhibits neuroblastoma cell growth. Anticancer Res 2008; 28(3A): 1509-16.
[PMID: 18630505]
Coulter DW, Wilkie MB, Moats-Staats BM. Inhibition of IGF-I receptor signaling in combination with rapamycin or temsirolimus increases MYC-N phosphorylation. Anticancer Res 2009; 29(6): 1943-9.
[PMID: 19528451]
Werner H, Maor S. The insulin-like growth factor-I receptor gene: A downstream target for oncogene and tumor suppressor action. Trends Endocrinol Metab 2006; 17(6): 236-42.
[] [PMID: 16815029]
Yu D, Watanabe H, Shibuya H, Miura M. The phosphatidylinositol-3 kinase pathway is not essential for insulin-like growth factor I receptor-mediated clonogenic radioresistance. J Radiat Res 2002; 43(3): 325-9.
[] [PMID: 12518992]
Héron-Milhavet L, Karas M, Goldsmith CM, Baum BJ, LeRoith D. Insulin-like growth factor-I (IGF-I) receptor activation rescues UV-damaged cells through a p38 signaling pathway. Potential role of the IGF-I receptor in DNA repair. J Biol Chem 2001; 276(21): 18185-92.
[] [PMID: 11278917]
Trojanek J, Ho T, Del Valle L, et al. Role of the insulin-like growth factor I/insulin receptor substrate 1 axis in Rad51 trafficking and DNA repair by homologous recombination. Mol Cell Biol 2003; 23(21): 7510-24.
[] [PMID: 14559999]
Cosaceanu D, Carapancea M, Castro J, et al. Modulation of response to radiation of human lung cancer cells following insulin-like growth factor 1 receptor inactivation. Cancer Lett 2005; 222(2): 173-81.
[] [PMID: 15863266]
Sutton P, Borgia JA, Bonomi P, Plate JMD. Lyn, a Src family kinase, regulates activation of epidermal growth factor receptors in lung adenocarcinoma cells. Mol Cancer 2013; 12(1): 76.
[] [PMID: 23866081]
Cosaceanu D, Budiu RA, Carapancea M, Castro J, Lewensohn R, Dricu A. Ionizing radiation activates IGF-1R triggering a cytoprotective signaling by interfering with Ku-DNA binding and by modulating Ku86 expression via a p38 kinase-dependent mechanism. Oncogene 2007; 26(17): 2423-34.
[] [PMID: 17043647]
Iyer R, Varela CR, Minturn JE, et al. AZ64 inhibits TrkB and enhances the efficacy of chemotherapy and local radiation in neuroblastoma xenografts. Cancer Chemother Pharmacol 2012; 70(3): 477-86.
[] [PMID: 22623209]
Qiu L, Zhou C, Sun Y, et al. Crosstalk between EGFR and TrkB enhances ovarian cancer cell migration and proliferation. Int J Oncol 2006; 29(4): 1003-11.
[] [PMID: 16964397]
Pandya CD, Pillai A. TrkB interacts with ErbB4 and regulates NRG1-induced NR2B phosphorylation in cortical neurons before synaptogenesis. Cell Commun Signal 2014; 12(1): 47.
[] [PMID: 25052836]
Choy C, Ansari KI, Neman J, et al. Cooperation of neurotrophin receptor TrkB and Her2 in breast cancer cells facilitates brain metastases. Breast Cancer Res 2017; 19(1): 51.
[] [PMID: 28446206]
Wu SL, Kim J, Bandle RW, Liotta L, Petricoin E, Karger BL. Dynamic profiling of the post-translational modifications and interaction partners of epidermal growth factor receptor signaling after stimulation by epidermal growth factor using Extended Range Proteomic Analysis (ERPA). Mol Cell Proteomics 2006; 5(9): 1610-27.
[] [PMID: 16799092]
Bielke W, Ziemieki A, Kappos L, Miescher GC. Expression of the B cell-associated tyrosine kinase gene Lyn in primary neuroblastoma tumours and its modulation during the differentiation of neuroblastoma cell lines. Biochem Biophys Res Commun 1992; 186(3): 1403-9.
[] [PMID: 1510669]
Palacios-Moreno J, Foltz L, Guo A, et al. Neuroblastoma tyrosine kinase signaling networks involve FYN and LYN in endosomes and lipid rafts. PLOS Comput Biol 2015; 11(4): e1004130.
[] [PMID: 25884760]
Layer PG, Kaulich S. Cranial nerve growth in birds is preceded by cholinesterase expression during neural crest cell migration and the formation of an HNK-1 scaffold. Cell Tissue Res 1991; 265(3): 393-407.
[] [PMID: 1723928]
Jin EJ, Ko HR, Hwang I, et al. Akt regulates neurite growth by phosphorylation-dependent inhibition of radixin proteasomal degradation. Sci Rep 2018; 8(1): 2557.
[] [PMID: 29416050]
López-Carballo G, Moreno L, Masiá S, Pérez P, Barettino D. Activation of the phosphatidylinositol 3-kinase/Akt signaling pathway by retinoic acid is required for neural differentiation of SH-SY5Y human neuroblastoma cells. J Biol Chem 2002; 277(28): 25297-304.
[] [PMID: 12000752]
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307(5712): 1098-101.
[] [PMID: 15718470]
Moysenovich AM, Tatarskiy VV, Yastrebova MA, et al. Akt and Src mediate the photocrosslinked fibroin-induced neural differentiation. Neuroreport 2020; 31(10): 770-5.
Mahajan K, Coppola D, Challa S, et al. Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One 2010; 5(3): e9646.
[] [PMID: 20333297]
Hu F, Liu H, Xie X, Mei J, Wang M. Activated cdc42-associated kinase is up-regulated in non-small-cell lung cancer and necessary for FGFR-mediated AKT activation. Mol Carcinog 2016; 55(5): 853-63.
[] [PMID: 25945695]
Ureña JM, La Torre A, Martínez A, et al. Expression, synaptic localization, and developmental regulation of Ack1/Pyk1, a cytoplasmic tyrosine kinase highly expressed in the developing and adult brain. J Comp Neurol 2005; 490(2): 119-32.
[] [PMID: 16052498]
La Torre A, del Mar Masdeu M, Cotrufo T, et al. A role for the tyrosine kinase ACK1 in neurotrophin signaling and neuronal extension and branching. Cell Death Dis 2013; 4(4): e602.
[] [PMID: 23598414]
Yang W, Lin Q, Zhao J, Guan JL, Cerione RA. The nonreceptor tyrosine kinase ACK2, a specific target for Cdc42 and a negative regulator of cell growth and focal adhesion complexes. J Biol Chem 2001; 276(47): 43987-93.
[] [PMID: 11535592]
Pao-Chun L, Chan PM, Chan W, Manser E. Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling. J Biol Chem 2009; 284(50): 34954-63.
[] [PMID: 19815557]
Salm F, Cwiek P, Ghosal A, et al. RNA interference screening identifies a novel role for autocrine fibroblast growth factor signaling in neuroblastoma chemoresistance. Oncogene 2013; 32(34): 3944-53.
[] [PMID: 23027129]
Yokoyama N, Miller WT. Biochemical properties of the Cdc42-associated tyrosine kinase ACK1. Substrate specificity, authphosphorylation, and interaction with Hck. J Biol Chem 2003; 278(48): 47713-23.
[] [PMID: 14506255]
Xu F, Li H, Sun Y. Inhibition of Axl improves the targeted therapy against ALK-mutated neuroblastoma. Biochem Biophys Res Commun 2014; 454(4): 566-71.
[] [PMID: 25450694]
a) R2: Genomics analysis and visualization platform. Available from:;
b) Gu L, Chu P, Lingeman R, McDaniel H, et al. The Mechanism by Which MYCN Amplification Confers an Enhanced Sensitivity to a PCNA-Derived Cell Permeable Peptide in Neuroblastoma Cells. EBioMedicine 2015; 2(12): 1923-31. Available from
Guiet R, Poincloux R, Castandet J, et al. Hematopoietic cell kinase (Hck) isoforms and phagocyte duties – From signaling and actin reorganization to migration and phagocytosis. Eur J Cell Biol 2008; 87(8-9): 527-42.
[] [PMID: 18538446]
Kim SO, Avraham S, Jiang S, Zagozdzon R, Fu Y, Avraham HK. Differential expression of Csk homologous kinase (CHK) in normal brain and brain tumors. Cancer 2004; 101(5): 1018-27.
[] [PMID: 15329911]
Yamashita H, Avraham S, Jiang S, Dikic I, Avraham H. The Csk homologous kinase associates with TrkA receptors and is involved in neurite outgrowth of PC12 cells. J Biol Chem 1999; 274(21): 15059-65.
[] [PMID: 10329710]
Kazi JU, Vaapil M, Agarwal S, Bracco E, Påhlman S, Rönnstrand L. The tyrosine kinase CSK associates with FLT3 and c-Kit receptors and regulates downstream signaling. Cell Signal 2013; 25(9): 1852-60.
[] [PMID: 23707526]
Vitali R, Cesi V, Nicotra MR, et al. c-Kit is preferentially expressed in MYCN -amplified neuroblastoma and its effect on cell proliferation is inhibited in vitro by STI-571. Int J Cancer 2003; 106(2): 147-52.
[] [PMID: 12800187]
Massoulié J, Bon S, Vigny M. The polymorphism of cholinesterase in vertebrates. Neurochem Int 1980; 2: 161-84.
[] [PMID: 20487781]
Massoulié J, Sussman J, Bon S, Silman I. Structure and functions of acetylcholinesterase and butyrylcholinesterase. Prog Brain Res. 1993; 98: p. 139-46.
[] [PMID: 8248501]
Leung MR, van Bezouwen LS, Schopfer LM, et al. Cryo-EM structure of the native butyrylcholinesterase tetramer reveals a dimer of dimers stabilized by a superhelical assembly. Proc Natl Acad Sci USA 2018; 115(52): 13270-5.
[] [PMID: 30538207]
Razon N, Soreq H, Roth E, Bartal A, Silman I. Characterization of activities and forms of cholinesterases in human primary brain tumors. Exp Neurol 1984; 84(3): 681-95.
[] [PMID: 6723888]
Montenegro MF, Ruiz-Espejo F, Campoy FJ, et al. Acetyl and butyrylcholinesterase activities decrease in human colon adenocarcinoma. J Mol Neurosci 2006; 30(1-2): 51-3.
[] [PMID: 17192624]
Ruiz-Espejo F, Cabezas-Herrera J, Illana J, Campoy FJ, Muñoz-Delgado E, Vidal CJ. Breast cancer metastasis alters acetylcholinesterase activity and the composition of enzyme forms in axillary lymph nodes. Breast Cancer Res Treat 2003; 80(1): 105-14.
[] [PMID: 12889604]
Sáez-Valero J, Vidal CJ. Biochemical properties of acetyl and butyrylcholinesterase in human meningioma. Biochim Biophys Acta Mol Basis Dis 1996; 1317(3): 210-8.
[] [PMID: 8988237]
Sáez-Valero J, Vidal CJ. Monomers and dimers of acetylcholinesterase in human meningioma are anchored to the membrane by glycosylphosphatidylinositol. Neurosci Lett 1995; 195(2): 101-4.
[] [PMID: 7478260]
Muñoz-Delgado E, Montenegro MF, Campoy FJ, et al. Expression of cholinesterases in human kidney and its variation in renal cell carcinoma types. FEBS J 2010; 277(21): 4519-29.
[] [PMID: 20883446]
Castillo-González AC, Nieto-Cerón S, Pelegrín-Hernández JP, et al. Dysregulated cholinergic network as a novel biomarker of poor prognostic in patients with head and neck squamous cell carcinoma. BMC Cancer 2015; 15(1): 385.
[] [PMID: 25956553]
Vidal CJ, Montenegro MF, Muñoz-Delgado E, Campoy FJ, Cabezas-Herrera J, Moral-Naranjo MT. The AChE membrane-binding tail PRiMA is down-regulated in muscle and nerve of mice with muscular dystrophy by merosin deficiency. Chem Biol Interact 2013; 203(1): 330-4.
[] [PMID: 22906800]
Lenfant N, Hotelier T, Velluet E, Bourne Y, Marchot P, Chatonnet A. ESTHER, the database of the α/β-hydrolase fold superfamily of proteins: Tools to explore diversity of functions. Nucleic Acids Res 2012; 41(D1): D423-9.
[] [PMID: 23193256]
Taylor P, De Jaco A, Comoletti D, Miller M, Camp S. Cholinesterase confabs and cousins: Approaching forty years. Chem Biol Interact 2013; 203(1): 10-3.
[] [PMID: 23085121]
Marchot P, Chatonnet A. Enzymatic activity and protein interactions in alpha/beta hydrolase fold proteins: Moonlighting versus promiscuity. Protein Pept Lett 2012; 19(2): 132-43.
[] [PMID: 21933125]
Lassmann T. Kalign 3: Multiple sequence alignment of large datasets. Bioinformatics 2019; 36(6): btz795.
[] [PMID: 31665271]
Lockridge O, Bartels CF, Vaughan TA, Wong CK, Norton SE, Johnson LL. Complete amino acid sequence of human serum cholinesterase. J Biol Chem 1987; 262(2): 549-57.
[] [PMID: 3542989]
Yen T, Nightingale BN, Burns JC, Sullivan DR, Stewart PM. Butyrylcholinesterase (BCHE) genotyping for post-succinylcholine apnea in an Australian population. Clin Chem 2003; 49(8): 1297-308.
[] [PMID: 12881446]
De Jaco A, Dubi N, Camp S, Taylor P. Congenital hypothyroidism mutations affect common folding and trafficking in the α/β-hydrolase fold proteins. FEBS J 2012; 279(23): 4293-305.
[] [PMID: 23035660]
Gjørlund MD, Nielsen J, Pankratova S, et al. Neuroligin - 1 induces neurite outgrowth through interaction with neurexin - 1β and activation of fibroblast growth factor receptor-1. FASEB J 2012; 26(10): 4174-86.
[] [PMID: 22750515]
Poulopoulos A, Soykan T, Tuffy LP, Hammer M, Varoqueaux F, Brose N. Homodimerization and isoform-specific heterodimerization of neuroligins. Biochem J 2012; 446(2): 321-30.
[] [PMID: 22671294]
Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 2005; 16(2): 139-49.
[] [PMID: 15863030]
Murray PB, Lax I, Reshetnyak A, et al. Heparin is an activating ligand of the orphan receptor tyrosine kinase ALK. Sci Signal 2015; 8(360): ra6.
[] [PMID: 25605972]
Pellegrini L, Burke DF, von Delft F, Mulloy B, Blundell TL. Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin. Nature 2000; 407(6807): 1029-34.
[] [PMID: 11069186]
Ibrahimi OA, Zhang F, Lang Hrstka SC, Mohammadi M, Linhardt RJ. Kinetic model for FGF, FGFR, and proteoglycan signal transduction complex assembly. Biochemistry 2004; 43(16): 4724-30.
[] [PMID: 15096041]
Sine JP, Colas B. Electrostatic interactions of the butyrylcholinesterase dimer of mucosal cells of rat intestine with glycosaminoglycans. Int J Biochem Cell Biol 1996; 28(5): 581-9.
[] [PMID: 8697103]
Sine JP, Toutant JP, Colas B. Butyrylcholinesterase amphiphilic forms of the mucosal cells of rat intestine bind heparin. Biochem Biophys Res Commun 1994; 201(3): 1376-81.
[] [PMID: 8024582]
Margalit H, Fischer N, Ben-Sasson SA. Comparative analysis of structurally defined heparin binding sequences reveals a distinct spatial distribution of basic residues. J Biol Chem 1993; 268(26): 19228-31.
[] [PMID: 8366075]
Fromm JR, Hileman RE, Caldwell EEO, Weiler JM, Linhardt RJ. Differences in the interaction of heparin with arginine and lysine and the importance of these basic amino acids in the binding of heparin to acidic fibroblast growth factor. Arch Biochem Biophys 1995; 323(2): 279-87.
[] [PMID: 7487089]
Fromm JR, Hileman RE, Caldwell EEO, Weiler JM, Linhardt RJ. Pattern and spacing of basic amino acids in heparin binding sites. Arch Biochem Biophys 1997; 343(1): 92-100.
[] [PMID: 9210650]
Esko JD. Proteins That Bind Sulfated Glycosaminoglycans. In: Essentials of Glycobiology. 2015; p. 493-502.
Zhong X, Arnolds O, Krenczyk O, et al. The structure in solution of fibronectin type III domain 14 reveals its synergistic heparin binding site. Biochemistry 2018; 57(42): 6045-9.
[] [PMID: 30260627]
Haupt H, Heide K, Zwisler O, Schwick HG. Isolation and physico-chemical characterization of cholinesterase in human serum. Blut 1966; 14(2): 65-75.
[] [PMID: 5928504]
Wellstein A. ALK receptor activation, ligands and therapeutic targeting in glioblastoma and in other cancers. Front Oncol 2012; 2: 192.
[] [PMID: 23267434]
Reshetnyak AV, Murray PB, Shi X, et al. Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand–receptor interactions. Proc Natl Acad Sci 2015; 112(52): 15862-7.
[] [PMID: 26630010]
Massoulié J, Perrier N, Noureddine H, Liang D, Bon S. Old and new questions about cholinesterases. Chem Biol Interact 2008; 175(1-3): 30-44.
[] [PMID: 18541228]
Cartaud A, Strochlic L, Guerra M, et al. MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction. J Cell Biol 2004; 165(4): 505-15.
[] [PMID: 15159418]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy