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http://dx.doi.org/10.5483/BMBRep.2021.54.7.048

The role of NUMB/NUMB isoforms in cancer stem cells  

Choi, Hye Yeon (Department of Molecular Microbiology and Immunology, University of Southern California)
Seok, Jaekwon (Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Konkuk University)
Kang, Geun-Ho (Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Konkuk University)
Lim, Kyung Min (Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Konkuk University)
Cho, Ssang-Goo (Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Konkuk University)
Publication Information
BMB Reports / v.54, no.7, 2021 , pp. 335-343 More about this Journal
Abstract
Cancer stem cells (CSCs) are a subpopulation of cancer that can self-renew and differentiate into large tumor masses. Evidence accumulated to date shows that CSCs affect tumor proliferation, recurrence, and resistance to chemotherapy. Recent studies have shown that, like stem cells, CSCs maintain cells with self-renewal capacity by means of asymmetric division and promote cell proliferation by means of symmetric division. This cell division is regulated by fate determinants, such as the NUMB protein, which recently has also been confirmed as a tumor suppressor. Loss of NUMB expression leads to uncontrolled proliferation and amplification of the CSC pool, which promotes the Notch signaling pathway and reduces the expression of the p53 protein. NUMB genes are alternatively spliced to produce six functionally distinct isoforms. An interesting recent discovery is that the protein NUMB isoform produced by alternative splicing of NUMB plays an important role in promoting carcinogenesis. In this review, we summarize the known functions of NUMB and NUMB isoforms related to the proliferation and generation of CSCs.
Keywords
Asymmetric cell division; Cancer stem cell (CSC); NOTCH signaling pathway; NUMB; NUMB isoforms;
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1 Salcini AE, Confalonieri S, Doria M et al (1997) Binding specificity and in vivo targets of the EH domain, a novel protein-protein interaction module. Genes Dev 11, 2239-2249   DOI
2 Verdi JM, Bashirullah A, Goldhawk DE et al (1999) Distinct human NUMB isoforms regulate differentiation vs. proliferation in the neuronal lineage. Proc Natl Acad Sci U S A 96, 10472-10476   DOI
3 Revil T, Gaffney D, Dias C, Majewski J and Jerome-Majewska LA (2010) Alternative splicing is frequent during early embryonic development in mouse. BMC Genomics 11, 399   DOI
4 Nilsen TW and Graveley BR (2010) Expansion of the eukaryotic proteome by alternative splicing. Nature 463, 457-463   DOI
5 Climente-Gonzalez H, Porta-Pardo E, Godzik A and Eyras E (2017) The functional impact of alternative splicing in cancer. Cell Rep 20, 2215-2226   DOI
6 Santolini E, Puri C, Salcini AE et al (2000) Numb is an endocytic protein. J Cell Biol 151, 1345-1352   DOI
7 Cayouette M and Raff M (2002) Asymmetric segregation of Numb: a mechanism for neural specification from Drosophila to mammals. Nat Neurosci 5, 1265-1269   DOI
8 Kahles A, Lehmann KV, Toussaint NC et al (2018) Comprehensive analysis of alternative splicing across tumors from 8,705 patients. Cancer Cell 34, 211-224 e216   DOI
9 Yang L, Shi P, Zhao G et al (2020) Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther 5, 8   DOI
10 Knoblich JA (2010) Asymmetric cell division: recent developments and their implications for tumour biology. Nat Rev Mol Cell Biol 11, 849-860   DOI
11 Najafi M, Mortezaee K and Ahadi R (2019) Cancer stem cell (a)symmetry & plasticity: tumorigenesis and therapy relevance. Life Sci 231, 116520   DOI
12 Plaks V, Kong N and Werb Z (2015) The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 16, 225-238   DOI
13 Gehring WJ (2004) Precis of Edwin G. Conklin's JEZ article, "Mosaic Development in Ascidian Eggs". J Exp Zool A Comp Exp Biol 301, 461-463   DOI
14 Morrison SJ and Kimble J (2006) Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441, 1068-1074   DOI
15 Santoro A, Vlachou T, Carminati M, Pelicci PG and Mapelli M (2016) Molecular mechanisms of asymmetric divisions in mammary stem cells. EMBO Rep 17, 1700-1720   DOI
16 Venkei ZG and Yamashita YM (2018) Emerging mechanisms of asymmetric stem cell division. J Cell Biol 217, 3785-3795   DOI
17 Sunchu B and Cabernard C (2020) Principles and mechanisms of asymmetric cell division. Development 147, dev167650   DOI
18 Dho SE, Jacob S, Wolting CD, French MB, Rohrschneider LR and McGlade CJ (1998) The mammalian numb phosphotyrosine-binding domain. Characterization of binding specificity and identification of a novel PDZ domaincontaining numb binding protein, LNX. J Biol Chem 273, 9179-9187   DOI
19 Zhong W, Feder JN, Jiang MM, Jan LY and Jan YN (1996) Asymmetric localization of a mammalian numb homolog during mouse cortical neurogenesis. Neuron 17, 43-53   DOI
20 Dho SE, French MB, Woods SA and McGlade CJ (1999) Characterization of four mammalian numb protein isoforms. Identification of cytoplasmic and membrane-associated variants of the phosphotyrosine binding domain. J Biol Chem 274, 33097-33104   DOI
21 Ntelios D, Berninger B and Tzimagiorgis G (2012) Numb and Alzheimer's disease: the current picture. Front Neurosci 6, 145   DOI
22 Siddique HR, Feldman DE, Chen CL, Punj V, Tokumitsu H and Machida K (2015) NUMB phosphorylation destabilizes p53 and promotes self-renewal of tumor-initiating cells by a NANOG-dependent mechanism in liver cancer. Hepatology 62, 1466-1479   DOI
23 Qi S, Zhao X, Li M et al (2015) Aberrant expression of Notch1/numb/snail signaling, an epithelial mesenchymal transition related pathway, in adenomyosis. Reprod Biol Endocrinol 13, 96   DOI
24 Luo Z, Mu L, Zheng Y et al (2020) NUMB enhances Notch signaling by repressing ubiquitination of NOTCH1 intracellular domain. J Mol Cell Biol 12, 345-358   DOI
25 Nowell CS and Radtke F (2017) Notch as a tumour suppressor. Nat Rev Cancer 17, 145-159   DOI
26 Kruse JP and Gu W (2009) Modes of p53 regulation. Cell 137, 609-622   DOI
27 Nag S, Qin J, Srivenugopal KS, Wang M and Zhang R (2013) The MDM2-p53 pathway revisited. J Biomed Res 27, 254-271   DOI
28 Wang Z, Sandiford S, Wu C and Li SS (2009) Numb regulates cell-cell adhesion and polarity in response to tyrosine kinase signalling. EMBO J 28, 2360-2373   DOI
29 Dho SE, Trejo J, Siderovski DP and McGlade CJ (2006) Dynamic regulation of mammalian numb by G protein-coupled receptors and protein kinase C activation: structural determinants of numb association with the cortical membrane. Mol Biol Cell 17, 4142-4155   DOI
30 Bolos V, Grego-Bessa J and de la Pompa JL (2007) Notch signaling in development and cancer. Endocr Rev 28, 339-363   DOI
31 Pece S, Confalonieri S, Romano PR and Di Fiore PP (2011) NUMB-ing down cancer by more than just a NOTCH. Biochim Biophys Acta 1815, 26-43
32 Wang Z, Li Y, Kong D and Sarkar FH (2010) The role of Notch signaling pathway in epithelial-mesenchymal transition (EMT) during development and tumor aggressiveness. Curr Drug Targets 11, 745-751   DOI
33 Leong KG and Karsan A (2006) Recent insights into the role of Notch signaling in tumorigenesis. Blood 107, 2223-2233   DOI
34 Bieging KT, Mello SS and Attardi LD (2014) Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer 14, 359-370   DOI
35 Steed E, Balda MS and Matter K (2010) Dynamics and functions of tight junctions. Trends Cell Biol 20, 142-149   DOI
36 Pece S, Serresi M, Santolini E et al (2004) Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol 167, 215-221   DOI
37 Colaluca IN, Tosoni D, Nuciforo P et al (2008) NUMB controls p53 tumour suppressor activity. Nature 451, 76-80   DOI
38 Westhoff B, Colaluca IN, D'Ario G et al (2009) Alterations of the Notch pathway in lung cancer. Proc Natl Acad Sci U S A 106, 22293-22298   DOI
39 Hong J, Liu Z, Zhu H et al (2014) The tumor suppressive role of NUMB isoform 1 in esophageal squamous cell carcinoma. Oncotarget 5, 5602-5614   DOI
40 Tosoni D, Zecchini S, Coazzoli M et al (2015) The Numb/p53 circuitry couples replicative self-renewal and tumor suppression in mammary epithelial cells. J Cell Biol 211, 845-862   DOI
41 Rajendran D, Zhang Y, Berry DM and McGlade CJ (2016) Regulation of Numb isoform expression by activated ERK signaling. Oncogene 35, 5202-5213   DOI
42 Langer W, Sohler F, Leder G et al (2010) Exon array analysis using re-defined probe sets results in reliable identification of alternatively spliced genes in non-small cell lung cancer. BMC Genomics 11, 676   DOI
43 Sato K, Watanabe T, Wang S et al (2011) Numb controls E-cadherin endocytosis through p120 catenin with aPKC. Mol Biol Cell 22, 3103-3119   DOI
44 Brooks MD, Burness ML and Wicha MS (2015) Therapeutic implications of cellular heterogeneity and plasticity in breast cancer. Cell Stem Cell 17, 260-271   DOI
45 Bani-Yaghoub M, Kubu CJ, Cowling R et al (2007) A switch in numb isoforms is a critical step in cortical development. Dev Dyn 236, 696-705   DOI
46 Verdi JM, Schmandt R, Bashirullah A et al (1996) Mammalian NUMB is an evolutionarily conserved signaling adapter protein that specifies cell fate. Curr Biol 6, 1134-1145   DOI
47 Dooley CM, James J, Jane McGlade C and Ahmad I (2003) Involvement of numb in vertebrate retinal development: evidence for multiple roles of numb in neural differentiation and maturation. J Neurobiol 54, 313-325   DOI
48 Majumdar S and Liu ST (2020) Cell division symmetry control and cancer stem cells. AIMS Mol Sci 7, 82-98   DOI
49 Badve S and Nakshatri H (2012) Breast-cancer stem cells-beyond semantics. Lancet Oncol 13, e43-48   DOI
50 Losick VP, Morris LX, Fox DT and Spradling A (2011) Drosophila stem cell niches: a decade of discovery suggests a unified view of stem cell regulation. Dev Cell 21, 159-171   DOI
51 Knoblich JA (2001) Asymmetric cell division during animal development. Nat Rev Mol Cell Biol 2, 11-20   DOI
52 Uemura T, Shepherd S, Ackerman L, Jan LY and Jan YN (1989) Numb, a gene required in determination of cell fate during sensory organ formation in Drosophila embryos. Cell 58, 349-360   DOI
53 Misquitta-Ali CM, Cheng E, O'Hanlon D et al (2011) Global profiling and molecular characterization of alternative splicing events misregulated in lung cancer. Mol Cell Biol 31, 138-150   DOI
54 Gulino A, Di Marcotullio L and Screpanti I (2010) The multiple functions of Numb. Exp Cell Res 316, 900-906   DOI
55 Zhao YJ, Han HZ, Liang Y, Shi CZ, Zhu QC and Yang J (2015) Alternative splicing of VEGFA, APP and NUMB genes in colorectal cancer. World J Gastroenterol 21, 6550-6560   DOI
56 Tarn WY, Kuo HC, Yu HI et al (2016) RBM4 promotes neuronal differentiation and neurite outgrowth by modulating Numb isoform expression. Mol Biol Cell 27, 1676-1683   DOI
57 Kyriazis GA, Wei Z, Vandermey M et al (2008) Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoform-dependent manner: implications for Alzheimer disease pathogenesis. J Biol Chem 283, 25492-25502   DOI
58 Shao X, Ding Z, Zhao M et al (2017) Mammalian Numb protein antagonizes Notch by controlling postendocytic trafficking of the Notch ligand Delta-like 4. J Biol Chem 292, 20628-20643   DOI
59 Kim KK, Nam J, Mukouyama YS and Kawamoto S (2013) Rbfox3-regulated alternative splicing of Numb promotes neuronal differentiation during development. J Cell Biol 200, 443-458   DOI
60 Flores AN, McDermott N, Meunier A and Marignol L (2014) NUMB inhibition of NOTCH signalling as a therapeutic target in prostate cancer. Nat Rev Urol 11, 499-507   DOI
61 Budillon A, Curley S, Fusco R and Mancini R (2019) Identification and targeting of stem cell-activated pathways in cancer therapy. Stem Cells Int 2019, 8549020
62 Artavanis-Tsakonas S, Rand MD and Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284, 770-776   DOI
63 Hori K, Sen A and Artavanis-Tsakonas S (2013) Notch signaling at a glance. J Cell Sci 126, 2135-2140   DOI
64 Guo M, Jan LY and Jan YN (1996) Control of daughter cell fates during asymmetric division: interaction of Numb and Notch. Neuron 17, 27-41   DOI
65 Frise E, Knoblich JA, Younger-Shepherd S, Jan LY and Jan YN (1996) The Drosophila Numb protein inhibits signaling of the Notch receptor during cell-cell interaction in sensory organ lineage. Proc Natl Acad Sci U S A 93, 11925-11932   DOI
66 Sciarrillo R, Wojtuszkiewicz A, Assaraf YG et al (2020) The role of alternative splicing in cancer: from oncogenesis to drug resistance. Drug Resist Updat 53, 100728   DOI
67 Schweisguth F (2004) Regulation of notch signaling activity. Curr Biol 14, R129-138   DOI
68 Yoo YD and Kwon YT (2015) Molecular mechanisms controlling asymmetric and symmetric self-renewal of cancer stem cells. J Anal Sci Technol 6, 28   DOI
69 Clevers H (2005) Stem cells, asymmetric division and cancer. Nat Genet 37, 1027-1028   DOI
70 Knoblich JA (2008) Mechanisms of asymmetric stem cell division. Cell 132, 583-597   DOI
71 Crawford TQ and Roelink H (2007) The notch response inhibitor DAPT enhances neuronal differentiation in embryonic stem cell-derived embryoid bodies independently of sonic hedgehog signaling. Dev Dyn 236, 886-892   DOI
72 Lu Y, Xu W, Ji J et al (2015) Alternative splicing of the cell fate determinant Numb in hepatocellular carcinoma. Hepatology 62, 1122-1131   DOI
73 Wai P, Truong B and Bhat KM (1999) Cell division genes promote asymmetric interaction between Numb and Notch in the Drosophila CNS. Development 126, 2759-2770   DOI
74 Brou C (2009) Intracellular trafficking of Notch receptors and ligands. Exp Cell Res 315, 1549-1555   DOI
75 Liu X, Xu QR, Xie WF and Wang MD (2014) DAPT suppresses the proliferation of human glioma cell line SHG-44. Asian Pac J Trop Med 7, 552-556   DOI
76 Karaczyn A, Bani-Yaghoub M, Tremblay R et al (2010) Two novel human NUMB isoforms provide a potential link between development and cancer. Neural Dev 5, 31   DOI
77 Karaczyn AA, Adams TL, Cheng RY, Matluk NN and Verdi JM (2017) Human NUMB6 induces epithelial-mesenchymal transition and enhances breast cancer cells migration and invasion. J Cell Biochem 118, 237-251   DOI
78 Li Y, Wang D, Wang H et al (2021) A splicing factor switch controls hematopoietic lineage specification of pluripotent stem cells. EMBO Rep 22, e50535
79 Wei R, Liu X, Voss C et al (2019) NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner. J Mol Cell Biol 11, 994-1005   DOI
80 Kavanaugh WM, Turck CW and Williams LT (1995) PTB domain binding to signaling proteins through a sequence motif containing phosphotyrosine. Science 268, 1177-1179   DOI