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A novel search engine for proteins involved in Notch crosstalk signaling pathways

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Abstract

To regulate biological activity in humans, the Notch signaling pathway (NSP) plays an essential role in a wide array of cellular development and differentiation process. In recent years, many studies have reported that aberrant activation of Notch is associated with the tumor process; but no appropriate database exists to fill this significant gap. To address this, we created a pioneering database NCSp, which is open access and comprises intercommunicating pathways and related protein mutations. This allows scientists to understand better the cause of single amino acid mutations in proteins. Therefore, NCSp provides information on the predicted functional effect of human protein mutations, which aids in understanding the importance of mutations linked to the Notch crosstalk signaling pathways in cancerous and non-cancerous systems. This database might be helpful for therapeutic mutation analysis, molecular biology, and structural biology researchers. The NCSp database can be accessed through https://bioserver3.physics.iisc.ac.in/cgi-bin/nccspd/.

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Abbreviations

AKT1:

RAC-alpha serine/threonine-protein kinase

AMPK:

adenosine monophosphate-activated protein kinase

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

ErbB-2:

epidermal growth factor receptor-2

GLI2:

GLI-Kruppel family member GLI2

Hh:

hedgehog

IKK:

IkappaB kinase

JAK-STAT:

janus kinases - signal transducer and activator of transcription proteins

KEGG:

Kyoto Encyclopedia of Genes and Genomes

KRAS:

GTPase KRas

MAPK:

mitogen-activated protein kinase

mTOR:

mammalian target of rapamycin

NCSp:

Notch crosstalk signaling pathway

NF-κB:

nuclear transcriptional factor kappa B

NFAT:

nuclear factors of activated T-cells

NICD:

Notch intracellular domain

NSP:

Notch signaling pathway

PI3K:

phosphatidylinositol-3-kinase

P53:

phosphoprotein 53

TGF-β:

transforming growth factor beta

TNF-α:

tumor necrosis factor-alpha

TCR:

T cell receptor

VEGF:

vascular endothelial growth factor

References

  • Adzhubei IA, Schmidt S, Peshkin L, et al. 2010 A method and server for predicting damaging missense mutations. Nat. Methods 7 248–249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aster JC, Pear WS and Blacklow SC 2017 The varied roles of Notch in cancer. Annu. Rev. Pathol. 12 245–275

    Article  CAS  PubMed  Google Scholar 

  • Bakr MN, Takahashi H and Kikuchi Y 2023 CHRNA1 and its correlated-myogenesis/cell cycle genes are prognosis-related markers of metastatic melanoma. Biochem. Biophys. Rep. 33 101425

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brandstadter JD and Maillard I 2019 Notch signalling in T cell homeostasis and differentiation. Open Biol. 9 190187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brzozowa-Zasada M, Piecuch A, Dittfeld A, et al. 2016 Notch signalling pathway as an oncogenic factor involved in cancer development. Contemp. Oncol. 20 267–272

    CAS  Google Scholar 

  • Choi Y, Sims GE, Murphy S, et al. 2012 Predicting the functional effect of amino acid substitutions and indels. PLoS One 7 e46688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Christopoulos PF, Gjølberg TT, Krüger S, et al. 2021 Targeting the Notch signaling pathway in chronic inflammatory diseases. Front. Immunol. 12 668207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Derynck R and Budi EH 2019 Specificity, versatility, and control of TGF-β family signaling. Sci. Signal. 12 5183

    Article  Google Scholar 

  • Espinosa L, Inglés-Esteve J, Aguilera C, et al. 2003 Phosphorylation by glycogen synthase kinase-3 beta downregulates Notch activity, a link for Notch and Wnt pathways. J. Biol. Chem. 22 278

    Google Scholar 

  • Espinoza I and Miele L 2013 Deadly crosstalk: Notch signaling at the intersection of EMT and cancer stem cells. Cancer Lett. 341 41–45

    Article  CAS  PubMed  Google Scholar 

  • Freeman-Cook KD, Autry C, Borzillo G, et al. 2010 Design of selective, ATP-competitive inhibitors of Akt. J. Med. Chem. 53 4615–4622

    Article  CAS  PubMed  Google Scholar 

  • Fullenkamp CA, Hall SL, Jaber OI, et al. 2016 TAZ and YAP are frequently activated oncoproteins in sarcomas. Oncotarget. 7 30094–30108

    Article  PubMed  PubMed Central  Google Scholar 

  • Guo S, Liu M and Gonzalez-Perez RR 2011 Role of Notch and its oncogenic signaling crosstalk in breast cancer. Biochim. Biophys. Acta 1815 197–213

    CAS  PubMed  Google Scholar 

  • Gustafsson MV, Zheng X, Pereira T, et al. 2005 Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev. Cell. 9 617–628

    Article  CAS  PubMed  Google Scholar 

  • Hanlon L, Avila JL, Demarest RM, et al. 2010 Notch1 functions as a tumor suppressor in a model of K-ras-induced pancreatic ductal adenocarcinoma. Cancer Res. 70 4280–4286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hansen CG, Moroishi T and Guan K-L 2015 YAP and TAZ: a nexus for Hippo signaling and beyond. Trends Cell Biol. 25 499–513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu X, Li J, Fu M, et al. 2021 The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct. Target Ther. 6 402

    Article  PubMed  PubMed Central  Google Scholar 

  • Jacobs CT and Huang P 2021 Complex crosstalk of Notch and Hedgehog signalling during the development of the central nervous system. Cell Mol. Life Sci. 78 635–644

    Article  CAS  PubMed  Google Scholar 

  • Kanehisa M 2002 The KEGG database; in ‘In Silico’ Simulation of biological processes: Novartis Foundation Symposium, volume 247 (Eds.) G Bock and JA Goode (Wiley) pp 91–103

  • Khan I and Ansari IA 2017 Prediction of a highly deleterious mutation E17K in AKT-1 gene: An in silico approach. Biochem. Biophys. Rep. 10 260–266

    PubMed  PubMed Central  Google Scholar 

  • Kondoh K, Sunadome K and Nishida E 2007 Notch signaling suppresses p38 MAPK activity via induction of MKP-1 in myogenesis. J. Biol. Chem. 282 3058–3065

    Article  CAS  PubMed  Google Scholar 

  • Kontomanolis EN, Kalagasidou S, Pouliliou S, et al. 2018 The notch pathway in breast cancer progression. Sci. World J. 2018 2415489

    Article  Google Scholar 

  • Lahiry M, Kumar S, Hari K, et al. 2020 AMPK-Fyn signaling promotes Notch1 stability to potentiate hypoxia-induced breast cancer stemness and drug resistance. https://doi.org/10.2139/ssrn.3586992

  • Lefort K, Mandinova A, Ostano P, et al. 2007 Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCK alpha kinases. Genes Dev. 21 562–577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li L, Tang P, Li S, et al. 2017 Notch signaling pathway networks in cancer metastasis: a new target for cancer therapy. Med. Oncol. 34 180

    Article  CAS  PubMed  Google Scholar 

  • Liu ZH, Dai XM and Du B 2015 Hes1: a key role in stemness, metastasis and multidrug resistance. Cancer Biol. Ther. 16 353–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Magrane M and Uniport Consortium 2011 UniProt Knowledgebase: a hub of integrated protein data. Database https://doi.org/10.1093/database/bar009

    Article  Google Scholar 

  • Mammucari C, di Vignano AT, Sharov AA, et al. 2005 Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control. Dev. Cell. 8 665–676

    Article  CAS  PubMed  Google Scholar 

  • Mehta K and Osipo C 2009 Trastuzumab resistance: Role for Notch signaling. Sci. World J. 9 1438–1448

    Article  CAS  Google Scholar 

  • Meurette O and Mehlen P 2018 Notch signaling in the tumor microenvironment. Cancer Cell. 34 536–548

    Article  CAS  PubMed  Google Scholar 

  • Misiorek JO, Przybyszewska-Podstawka A, Kałafut J, Paziewska B, Rolle K, Rivero-Müller A and Nees M 2021 Context matters: NOTCH signatures and pathway in cancer progression and metastasis. Cells 10 94

  • O’Brien KA, Murray AJ and Simonson TS 2022. Notch signaling and cross-talk in hypoxia: a candidate pathway for high-altitude adaptation. Life 12 437

  • Oeckinghaus A, Hayden MS and Ghosh S 2011 Crosstalk in NF-κB signaling pathways. Nat. Immunol. 12 695–708

    Article  CAS  PubMed  Google Scholar 

  • Osipo C, Golde TE, Osborne BA, et al. 2008 Off the beaten pathway: the complex cross talk between Notch and NF- kappaB. Lab. Invest. 88 11–17

    Article  CAS  PubMed  Google Scholar 

  • Pancewicz-Wojtkiewicz J 2016 Epidermal growth factor receptor and notch signaling in non-small-cell lung cancer. Cancer Med. 5 3572–3578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patni AP, Harishankar MK, Joseph JP, et al. 2021 Comprehending the crosstalk between Notch, Wnt and Hedgehog signaling pathways in oral squamous cell carcinoma - clinical implications. Cell Oncol. 44 473–494

    Article  CAS  Google Scholar 

  • Pereira F, Ferreira A, Reis CA, et al. 2022 KRAS as a modulator of the inflammatory tumor microenvironment: Therapeutic implications. Cells 11 398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ranganathan P, Weaver KL and Capobianco AJ 2011 Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer. 11 338–351

    Article  CAS  PubMed  Google Scholar 

  • Reedijk M 2012 Notch signaling and breast cancer. Adv. Exp. Med. Biol. 727 241–257

    Article  CAS  PubMed  Google Scholar 

  • Reicher A, Foßelteder J, Kwong LN, et al. 2018 Crosstalk between the Notch signaling pathway and long non-coding RNAs. Cancer Lett. 420 91–96

    Article  CAS  PubMed  Google Scholar 

  • Reva B, Antipin Y and Sander C 2011 Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res. 39 e118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sam SA, Teel J, Tegge AN, et al. 2017 XTalkDB: a database of signaling pathway crosstalk. Nucleic Acids Res. 45 D432–D439

    Article  CAS  PubMed  Google Scholar 

  • Shimobayashi M and Hall MN 2014 Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat. Rev. Mol. Cell Biol. 15 155–162

    Article  CAS  PubMed  Google Scholar 

  • Siebel C and Lendahl U 2017 Notch signaling in development, tissue homeostasis, and disease. Physiol. Rev. 97 1235–1294

    Article  CAS  PubMed  Google Scholar 

  • Song H, Wang Y, Lan H, et al. 2018 Expression of Notch receptors and their ligands in pancreatic ductal adenocarcinoma. Exp. Ther. Med. 16 53–60

    PubMed  PubMed Central  Google Scholar 

  • Sun G, Shan MH, Ma BL, et al. 2012 Identifying crosstalk of mTOR signaling pathway of lobular breast carcinomas. Eur. Rev. Med. Pharmacol. Sci. 16 1355–1361

    CAS  PubMed  Google Scholar 

  • Sundaram MV 2005 The love-hate relationship between Ras and Notch. Genes Dev. 19 1825–1839

    Article  CAS  PubMed  Google Scholar 

  • Takebe N, Harris PJ, Warren RQ, et al. 2011 Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat. Rev. Clin. Oncol. 8 97–106

    Article  CAS  PubMed  Google Scholar 

  • Tang H and Thomas PD 2016 PANTHER-PSEP: predicting disease-causing genetic variants using position-specific evolutionary preservation. Bioinformatics 32 2230–2232

    Article  CAS  PubMed  Google Scholar 

  • Tocharoentanaphol C, Promso S, Zelenika D, et al. 2008 Evaluation of resequencing on number of tag SNPs of 13 atherosclerosis-related genes in Thai population. J. Hum. Genet. 53 74–86

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Wang D, Dai Y, et al. 2021 Positive crosstalk between Hedgehog and NF-κB pathways is dependent on KRAS mutation in pancreatic ductal adenocarcinoma. Front. Oncol. 11 652283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Welcker M and Clurman BE 2008 FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat. Rev. Cancer 8 83–93

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi N, Oyama T, Ito E, et al. 2008 NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells. Cancer Res. 68 1881–1888

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors (KS, SR and DR) thank the ‘An Indian Initiative on setting up a high-fidelity structural data archival/retrieval system for Life Sciences-(PDBi)’ project, funded by CDAC (Center for Development of Advanced Computing). JJ and MS acknowledge the MHRD-RUSA 2.0, (F.24-51/2014-U, Policy (TN Multi-Gen), Department of Education, Government of India (Dt.09.10.2018). JJ acknowledges the financial grant supported by DBT-BIC (BT/PR40154/BTIS/137/34/2021, Dt. 07.03.2022). CNR acknowledges the Dr. D.S. Kothari Postdoctoral Fellowship (DSKPDF) (Ref.No. BL/20-21/0172 (S-90)), funded by the University Grants Commission (UGC). Also, the funding by the Department of Biotechnology (DBT) is gratefully acknowledged.

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Authors

Contributions

JJ conceptualised the problem. MS and SR devised the methodology. MS and DR designed the front end of the database. MS and CNR wrote the manuscript. KS reviewed the manuscript.

Corresponding authors

Correspondence to Jeyakanthan Jeyaraman or Sekar Kanagaraj.

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The authors have no conflicts of interest to disclose.

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Corresponding editor: Susmita Roy

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Sanjeevi, M., Rajendran, S., Ramachandran, D. et al. A novel search engine for proteins involved in Notch crosstalk signaling pathways. J Biosci 49, 8 (2024). https://doi.org/10.1007/s12038-023-00395-7

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