Skip to main content
SpringerLink
Log in

An assembly of TROP2-mediated signaling events

  • Nuts and bolts
  • Published:
Journal of Cell Communication and Signaling Aims and scope

Abstract

Trophoblast cell surface antigen 2 (TROP2) is a calcium-transducing transmembrane protein mainly involved in embryo development. The aberrant expression of TROP2 is observed in numerous cancers, including triple-negative breast cancer, gastric, colorectal, pancreatic, squamous cell carcinoma of the oral cavity, and prostate cancers. The main signaling pathways mediated by TROP2 are calcium signaling, PI3K/AKT, JAK/STAT, MAPKs, and β-catenin signaling. However, collective information about the TROP2-mediated signaling pathway is not available for visualization or analysis. In this study, we constructed a TROP2 signaling map with respect to its role in different cancers. The data curation was done manually by following the NetPath annotation criteria. The described map consists of different molecular events, including 8 activation/inhibition, 16 enzyme catalysis, 19 gene regulations, 12 molecular associations, 39 induced-protein expressions, and 2 protein translocation. The data of the TROP2 pathway map is made freely accessible through the WikiPathways Database (https://www.wikipathways.org/index.php/Pathway:WP5300).

Graphical abstract

Development of TROP2 signaling pathway map

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  • Abhinand CS, Raju R, Soumya SJ, Arya PS, Sudhakaran PR (2016) VEGF-A/VEGFR2 signaling network in endothelial cells relevant to angiogenesis. J Cell Commun Signal 10(4):347–354

    Article  PubMed  PubMed Central  Google Scholar 

  • Aravind A, Palollathil A, Rex DAB, Kumar KMK, Vijayakumar M, Shetty R, Codi JAK, Prasad TSK, Raju R (2022) A multi-cellular molecular signaling and functional network map of C-C motif chemokine ligand 18 (CCL18): a chemokine with immunosuppressive and pro-tumor functions. J Cell Commun Signal 16(2):293–300

    Article  CAS  PubMed  Google Scholar 

  • Bardia A, Messersmith WA, Kio EA, Berlin JD, Vahdat L, Masters GA, Moroose R, Santin AD, Kalinsky K, Picozzi V, O’Shaughnessy J, Gray JE, Komiya T, Lang JM, Chang JC, Starodub A, Goldenberg DM, Sharkey RM, Maliakal P, Hong Q, Wegener WA, Goswami T, Ocean AJ (2021) Sacituzumab govitecan, a trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol 32(6):746–756

    Article  CAS  PubMed  Google Scholar 

  • Calabrese G, Crescenzi C, Morizio E, Palka G, Guerra E, Alberti S (2001) Assignment of TACSTD1 (alias TROP1, M4S1) to human chromosome 2p21 and refinement of mapping of TACSTD2 (alias TROP2, M1S1) to human chromosome 1p32 by in situ hybridization. Cytogenet Cell Genet 92(1–2):164–165

    Article  CAS  PubMed  Google Scholar 

  • Cubas R, Li M, Chen C, Yao Q (2009) TROP2: a possible therapeutic target for late stage epithelial carcinomas. Biochim Biophys Acta 1796(2):309–314

    CAS  PubMed  Google Scholar 

  • Cubas R, Zhang S, Li M, Chen C, Yao Q (2010) TROP2 expression contributes to tumor pathogenesis by activating the ERK MAPK pathway. Mol Cancer 9:253

    Article  PubMed  PubMed Central  Google Scholar 

  • Dagamajalu S, Rex DAB, Palollathil A, Shetty R, Bhat G, Cheung LWT, Prasad TSK (2021) Correction to: a pathway map of AXL receptor-mediated signaling network. J Cell Commun Signal 15(1):149

    Article  CAS  PubMed  Google Scholar 

  • Fong D, Moser P, Krammel C, Gostner JM, Margreiter R, Mitterer M, Gastl G, Spizzo G (2008) High expression of TROP2 correlates with poor prognosis in pancreatic cancer. Br J Cancer 99(8):1290–1295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goldenberg DM, Stein R, Sharkey RM (2018) The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget 9(48):28989–29006

    Article  PubMed  PubMed Central  Google Scholar 

  • Gu QZ, Nijiati A, Gao X, Tao KL, Li CD, Fan XP, Tian Z (2018) TROP2 promotes cell proliferation and migration in osteosarcoma through PI3K/AKT signaling. Mol Med Rep 18(2):1782–1788

    CAS  PubMed  Google Scholar 

  • Guan H, Guo Z, Liang W, Li H, Wei G, Xu L, Xiao H, Li Y (2017) TROP2 enhances invasion of thyroid cancer by inducing MMP2 through ERK and JNK pathways. BMC Cancer 17(1):486

    Article  PubMed  PubMed Central  Google Scholar 

  • Guerra E, Trerotola M, Aloisi AL, Tripaldi R, Vacca G, La Sorda R, Lattanzio R, Piantelli M, Alberti S (2013) The trop-2 signalling network in cancer growth. Oncogene 32(12):1594–1600

    Article  CAS  PubMed  Google Scholar 

  • Guerra E, Trerotola M, Tripaldi R, Aloisi AL, Simeone P, Sacchetti A, Relli V, D’Amore A, La Sorda R, Lattanzio R, Piantelli M, Alberti S (2016) Trop-2 induces tumor growth through AKT and determines sensitivity to AKT inhibitors. Clin Cancer Res 22(16):4197–4205

    Article  CAS  PubMed  Google Scholar 

  • Guerra E, Trerotola M, Relli V, Lattanzio R, Tripaldi R, Vacca G, Ceci M, Boujnah K, Garbo V, Moschella A, Zappacosta R, Simeone P, de Lange R, Weidle UH, Rotelli MT, Picciariello A, Depalo R, Querzoli P, Pedriali M, Bianchini E, Angelucci D, Pizzicannella G, Di Loreto C, Piantelli M, Antolini L, Sun XF, Altomare DF, Alberti S (2021) Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer. Neoplasia 23(9):898–911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo X, Zhu X, Zhao L, Li X, Cheng D, Feng K (2017) Tumor-associated calcium signal transducer 2 regulates neovascularization of non-small-cell lung cancer via activating ERK1/2 signaling pathway. Tumour Biol 39(3):1010428317694324

    Article  PubMed  Google Scholar 

  • Hou J, Lv A, Deng Q, Zhang G, Hu X, Cui H (2019) TROP2 promotes the proliferation and metastasis of glioblastoma cells by activating the JAK2/STAT3 signaling pathway. Oncol Rep 41(2):753–764

    CAS  PubMed  Google Scholar 

  • Howland JG, Wang YT (2008) Synaptic plasticity in learning and memory: stress effects in the hippocampus. Prog Brain Res 169:145–158

    Article  CAS  PubMed  Google Scholar 

  • Hsu EC, Rice MA, Bermudez A, Marques FJG, Aslan M, Liu S, Ghoochani A, Zhang CA, Chen YS, Zlitni A, Kumar S, Nolley R, Habte F, Shen M, Koul K, Peehl DM, Zoubeidi A, Gambhir SS, Kunder CA, Pitteri SJ, Brooks JD, Stoyanova T (2020) TROP2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1. Proc Natl Acad Sci U S A 117(4):2032–2042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jia L, Wang T, Ding G, Kuai X, Wang X, Wang B, Zhao W, Zhao Y (2020) TROP2 inhibition of P16 expression and the cell cycle promotes intracellular calcium release in OSCC. Int J Biol Macromol 164:2409–2417

    Article  CAS  PubMed  Google Scholar 

  • Ju X, Jiao X, Ertel A, Casimiro MC, Di Sante G, Deng S, Li Z, Di Rocco A, Zhan T, Hawkins A, Stoyanova T, Ando S, Fatatis A, Lisanti MP, Gomella LG, Languino LR, Pestell RG (2016) v-Src oncogene induces TROP2 proteolytic activation via cyclin D1. Cancer Res 76(22):6723–6734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GS, Venugopal AK, Telikicherla D, Navarro JD, Mathivanan S, Pecquet C, Gollapudi SK, Tattikota SG, Mohan S, Padhukasahasram H, Subbannayya Y, Goel R, Jacob HK, Zhong J, Sekhar R, Nanjappa V, Balakrishnan L, Subbaiah R, Ramachandra YL, Rahiman BA, Prasad TS, Lin JX, Houtman JC, Desiderio S, Renauld JC, Constantinescu SN, Ohara O, Hirano T, Kubo M, Singh S, Khatri P, Draghici S, Bader GD, Sander C, Leonard WJ, Pandey A (2010) NetPath: a public resource of curated signal transduction pathways. Genome Biol 11(1):R3

    Article  PubMed  PubMed Central  Google Scholar 

  • Kuai X, Jia L, Yang T, Huang X, Zhao W, Zhang M, Chen Y, Zhu J, Feng Z, Tang Q (2020) TROP2 promotes multidrug resistance by regulating notch1 signaling pathway in gastric cancer cells. Med Sci Monit 26:e919566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kushiyama S, Yashiro M, Yamamoto Y, Sera T, Sugimoto A, Nishimura S, Togano S, Kuroda K, Yoshii M, Tamura T, Toyokawa T, Tanaka H, Muguruma K, Nakada H, Ohira M (2021) Clinicopathologic significance of TROP2 and phospho-TROP2 in gastric cancer. Mol Clin Oncol 14(5):105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kutmon M, van Iersel MP, Bohler A, Kelder T, Nunes N, Pico AR, Evelo CT (2015) PathVisio 3: an extendable pathway analysis toolbox. PLoS Comput Biol 11(2):e1004085

    Article  PubMed  PubMed Central  Google Scholar 

  • Li X, Teng S, Zhang Y, Zhang W, Zhang X, Xu K, Yao H, Yao J, Wang H, Liang X, Hu Z (2017) TROP2 promotes proliferation, migration and metastasis of gallbladder cancer cells by regulating PI3K/AKT pathway and inducing EMT. Oncotarget 8(29):47052–47063

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin JC, Wu YY, Wu JY, Lin TC, Wu CT, Chang YL, Jou YS, Hong TM, Yang PC (2012) TROP2 is epigenetically inactivated and modulates IGF-1R signalling in lung adenocarcinoma. EMBO Mol Med 4(6):472–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Linnenbach AJ, Wojcierowski J, Wu SA, Pyrc JJ, Ross AH, Dietzschold B, Speicher D, Koprowski H (1989) Sequence investigation of the major gastrointestinal tumor-associated antigen gene family, GA733. Proc Natl Acad Sci U S A 86(1):27–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lipinski M, Parks DR, Rouse RV, Herzenberg LA (1981) Human trophoblast cell-surface antigens defined by monoclonal antibodies. Proc Natl Acad Sci U S A 78(8):5147–5150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu T, Liu Y, Bao X, Tian J, Liu Y, Yang X (2013) Overexpression of TROP2 predicts poor prognosis of patients with cervical cancer and promotes the proliferation and invasion of cervical cancer cells by regulating ERK signaling pathway. PLoS ONE 8(9):e75864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mori Y, Akita K, Ojima K, Iwamoto S, Yamashita T, Morii E, Nakada H (2019) Trophoblast cell surface antigen 2 (Trop-2) phosphorylation by protein kinase C alpha/delta (PKCalpha/delta) enhances cell motility. J Biol Chem 294(30):11513–11524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mustata RC, Vasile G, Fernandez-Vallone V, Strollo S, Lefort A, Libert F, Monteyne D, Perez-Morga D, Vassart G, Garcia MI (2013) Identification of Lgr5-independent spheroid-generating progenitors of the mouse fetal intestinal epithelium. Cell Rep 5(2):421–432

    Article  CAS  PubMed  Google Scholar 

  • Pavsic M (2021) TROP2 forms a stable dimer with significant structural differences within the membrane-distal region as compared to EpCAM. Int J Mol Sci 22(19):10640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raju R, Palapetta SM, Sandhya VK, Sahu A, Alipoor A, Balakrishnan L, Advani J, George B, Kini KR, Geetha NP, Prakash HS, Prasad TS, Chang YJ, Chen L, Pandey A, Gowda H (2014) A network map of FGF-1/FGFR Signaling System. J Signal Transduct 2014:962962

    Article  PubMed  PubMed Central  Google Scholar 

  • Rex DAB, Agarwal N, Prasad TSK, Kandasamy RK, Subbannayya Y, Pinto SM (2020) A comprehensive pathway map of IL-18-mediated signalling. J Cell Commun Signal 14(2):257–266

    Article  CAS  PubMed  Google Scholar 

  • Ripani E, Sacchetti A, Corda D, Alberti S (1998) Human trop-2 is a tumor-associated calcium signal transducer. Int J Cancer 76(5):671–676

    Article  CAS  PubMed  Google Scholar 

  • Shvartsur A, Bonavida B (2015) TROP2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes Cancer 6(3–4):84–105

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sin STK, Li Y, Liu M, Ma S, Guan XY (2019) TROP-2 exhibits tumor suppressive functions in cervical cancer by dual inhibition of IGF-1R and ALK signaling. Gynecol Oncol 152(1):185–193

    Article  CAS  PubMed  Google Scholar 

  • Stoyanova T, Goldstein AS, Cai H, Drake JM, Huang J, Witte ON (2012) Regulated proteolysis of TROP2 drives epithelial hyperplasia and stem cell self-renewal via beta-catenin signaling. Genes Dev 26(20):2271–2285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun X, Jia L, Wang T, Zhang Y, Zhao W, Wang X, Chen H (2021) TROP2 binding IGF2R induces gefitinib resistance in NSCLC by remodeling the tumor microenvironment. J Cancer 12(17):5310–5319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang G, Tang Q, Jia L, Chen Y, Lin L, Kuai X, Gong A, Feng Z (2019) TROP2 increases growth and metastasis of human oral squamous cell carcinoma through activation of the PI3K/Akt signaling pathway. Int J Mol Med 44(6):2161–2170

    CAS  PubMed  PubMed Central  Google Scholar 

  • Trerotola M, Li J, Alberti S, Languino LR (2012) Trop-2 inhibits prostate cancer cell adhesion to fibronectin through the beta1 integrin-RACK1 axis. J Cell Physiol 227(11):3670–3677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trerotola M, Jernigan DL, Liu Q, Siddiqui J, Fatatis A, Languino LR (2013) Trop-2 promotes prostate cancer metastasis by modulating beta(1) integrin functions. Cancer Res 73(10):3155–3167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trerotola M, Ganguly KK, Fazli L, Fedele C, Lu H, Dutta A, Liu Q, De Angelis T, Riddell LW, Riobo NA, Gleave ME, Zoubeidi A, Pestell RG, Altieri DC, Languino LR (2015) Trop-2 is up-regulated in invasive prostate cancer and displaces FAK from focal contacts. Oncotarget 6(16):14318–14328

    Article  PubMed  PubMed Central  Google Scholar 

  • Trerotola M, Guerra E, Ali Z, Aloisi AL, Ceci M, Simeone P, Acciarito A, Zanna P, Vacca G, D’Amore A, Boujnah K, Garbo V, Moschella A, Lattanzio R, Alberti S (2021) Trop-2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis. Neoplasia 23(4):415–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vranic S, Gatalica Z (2022) Trop-2 protein as a therapeutic target: a focused review on Trop-2-based antibody-drug conjugates and their predictive biomarkers. Bosn J Basic Med Sci 22(1):14–21

    CAS  PubMed  Google Scholar 

  • Wang M, Guo Y, Wang M, Zhou T, Xue Y, Du G, Wei X, Wang J, Qi L, Zhang H, Li L, Ye L, Guo X, Wu X (2017) The glial cell-derived neurotrophic factor (GDNF)-responsive phosphoprotein landscape identifies raptor phosphorylation required for spermatogonial progenitor cell proliferation. Mol Cell Proteomics 16(6):982–997

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao W, Zhu H, Zhang S, Yong H, Wang W, Zhou Y, Wang B, Wen J, Qiu Z, Ding G, Feng Z, Zhu J (2016) TROP2 is overexpressed in gastric cancer and predicts poor prognosis. Oncotarget 7(5):6136–6145

    Article  PubMed  Google Scholar 

  • Zhao W, Kuai X, Zhou X, Jia L, Wang J, Yang X, Tian Z, Wang X, Lv Q, Wang B, Zhao Y, Huang W (2018) TROP2 is a potential biomarker for the promotion of EMT in human breast cancer. Oncol Rep 40(2):759–766

    CAS  PubMed  Google Scholar 

  • Zhao W, Jia L, Kuai X, Tang Q, Huang X, Yang T, Qiu Z, Zhu J, Huang J, Huang W, Feng Z (2019) The role and molecular mechanism of TROP2 induced epithelial-mesenchymal transition through mediated beta-catenin in gastric cancer. Cancer Med 8(3):1135–1147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zuo T, Qin JY, Chen J, Shi Z, Liu M, Gao X, Gao D (2013) Involvement of N-cadherin in the protective effect of glial cell line-derived neurotrophic factor on dopaminergic neuron damage. Int J Mol Med 31(3):561–568

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Karnataka Biotechnology and Information Technology Services (KBITS), Government of Karnataka, India, for the support to Center for Systems Biology and Molecular Medicine at Yenepoya (Deemed to be University) under the Biotechnology Skill Enhancement Programme in Multiomics Technology (BiSEP GO ITD 02 MDA 2017). Rajesh Raju is a recipient of the Young Scientist Award (YSS/2014/000607) from the Science and Engineering Research Board, Department of Science and Technology (DST), Government of India.

Author information

Authors and Affiliations

  1. Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to Be University), Mangalore, 575018, India

    Shubham Sukerndeo Upadhyay, Sakshi Sanjay Parate, Shobha Dagamajalu, T. S. Keshava Prasad & Rajesh Raju

  2. Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, 575018, India

    Rex Devasahayam Arokia Balaya & Rajesh Raju

  3. Department of Surgical Oncology, Yenepoya Medical College Hospital, Yenepoya (Deemed to Be University), Mangalore, 575018, India

    Rohan Shetty

Authors
  1. Shubham Sukerndeo Upadhyay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rex Devasahayam Arokia Balaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sakshi Sanjay Parate
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shobha Dagamajalu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. S. Keshava Prasad
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rohan Shetty
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rajesh Raju
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Rex Devasahayam Arokia Balaya, Rohan Shetty or Rajesh Raju.

Ethics declarations

Conflict of interest

The authors report no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLSX 52 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Upadhyay, S.S., Devasahayam Arokia Balaya, R., Parate, S.S. et al. An assembly of TROP2-mediated signaling events. J. Cell Commun. Signal. 17, 1105–1111 (2023). https://doi.org/10.1007/s12079-023-00742-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12079-023-00742-1

Keywords

Search

Navigation