TROP2 regulatory signaling (Homo sapiens)

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11TACSTD2351, 6151720, 4042112InHCT116cellsTROP2dimerTROP2 prevents IGF1 & MDKbinding to IGF1R &ALK, respectively, bycompetitive binding Up-regulationIntracellular(TROP2-ICD)In the leading edges of prostate cancer cells plated on FN In LNCaP cells and xenograftsleading toDNA condensationand decrease inhistone methylationInHUVECsProteinEnhanceddirectionalmigrationInMTE-4-14 cellsIn GBC-SD andSGC-996 cellsEnhancesGC cell tolerance tochemotherapy35, 37Ca2+CLDN1CLDN734PARP1CD56PSMAPSASOX2MYCTP63OCT3/4ARUpregulatedin VCaP cells &downregulatedin LNCaP cells& 22Rv1 cells SYPInLNCaPandPC-3cells 3434ABCC1NOTCH1In BGC-823 andHGC27 cells 2222222224CDKN2A2424Cell cycleregulationPRKAA224PIK3R1PAKT1T308S4732626, 28, 3928Proliferation and migrationof HN6, SCC4,MG63, KM12SMMNNG/HOS, U2OS,MTE4-14 andPC-9/GR cells10, 26, 28MMP241In 8505C,K1 andFT-133 cellsAP14112, 41MAPK8MAPK9Y185T183Y185T183MAPK1MAPK3Y187T185Y204T20213, 19, 21, 40, 414141PTENS380PDPK139393939IGF18, 118, 11MDK894, 9PRKCAPRKCD4CASP321In A549NSCLCs21MMP1321PECAM1EGFRY1173In A549NSCLCs21ACVRL1IGF1RY1604Y1151Y1150Y1135Y113688888, 19InHeLacells88RAC1GTP11ITGB1ITGA51, 6TLN1TLN1119, 40CREB1S133STAT1Y701RB1S780NFKB112SRCPTK2Y416Y397InPC3-2cellsJUNIn FT-133,FADU andMTE-4-14 cellsADAM10 25TACSTD2S32217CDH1Affinity:CLDN7>CLDN1BCL25, 18BAXInA2780,Hela and C33AcellsCTNNB17, 13FN1VIMCDH1Induces EMTin MGC803cells5, 13CDK4InHelaandC33Acells13In LNCaP &TRAMP C2 cells36CCND1CCNE1CDK2CDKN1BInPanc02, Hela and C33AcellsJAK2Y1008STAT3Y1007S727Y705141414In LN-229and U87-MGcellsPSEN2ADAM17 1515TACSTD2TROP2-ICD15PSEN1 ADAM17 153, 15In LNCaPcells 15153655Upregulatedin Panc02, Hela,C33ATRAMP C2 &HEP2 cells anddown-regulatedin MTE-4-14 cells34343434InLNCaP,PC-3,VCaP,DU-145cells34In LNCaP cells and xenografts,PC-3, andVCaP cells3434343434CTNNB171111In TROP2-overexpressingH1299,CL1-0and H23 lungcancer cells11In TROP2-overexpressingH1299,CL1-0and H23 lungcancer cells1111InH1299 andH23 cellsIGF2RIGF210101010RACK1121212391219, 403419CYNUCYNUFACEIn MTE-4-14 cells191919, 4021mRNAProteinmRNAProteinmRNA Down-regulationProtein Components of complex unknownCa2+ Calcium ionProteinProtein Proteins in complexProteinXXXX Proteins with/without phosphositeFACECYNUTROP2-ICD TROP2 intracellular domain Protein-protein interaction Kinase-substrate reaction Leads to through unknown mechanisms or indication of studied cell types Leads to decrease in activity or phosphorylation at sites Translocation of proteins Transcriptional or translational regulation of gene/protein expression Cytoplasm Cell leading edges Focal adhesions Nucleus Figure Legend TROP2 Regulatory signaling networkPAK4S4741115NUMBIn v-SRC PECcells 1539


Schematic representation of TROP2 mediated signaling mechanism in different types of cancers

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  1. Trerotola M, Jernigan DL, Liu Q, Siddiqui J, Fatatis A, Languino LR; ''Trop-2 promotes prostate cancer metastasis by modulating β(1) integrin functions.''; Cancer Res, 2013 PubMed Europe PMC Scholia
  2. Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Goldenberg DM; ''Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys.''; Clin Cancer Res, 2011 PubMed Europe PMC Scholia
  3. Wang XD, Wang Q, Chen XL, Huang JF, Yin Y, Da P, Wu H; ''Trop2 inhibition suppresses the proliferation and invasion of laryngeal carcinoma cells via the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway.''; Mol Med Rep, 2015 PubMed Europe PMC Scholia
  4. Mori Y, Akita K, Ojima K, Iwamoto S, Yamashita T, Morii E, Nakada H; ''Trophoblast cell surface antigen 2 (Trop-2) phosphorylation by protein kinase C α/δ (PKCα/δ) enhances cell motility.''; J Biol Chem, 2019 PubMed Europe PMC Scholia
  5. Liu T, Liu Y, Bao X, Tian J, Yang X; ''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, 2013 PubMed Europe PMC Scholia
  6. 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; ''Trop-2 is up-regulated in invasive prostate cancer and displaces FAK from focal contacts.''; Oncotarget, 2015 PubMed Europe PMC Scholia
  7. Zhao W, Jia L, Kuai X, Tang Q, Huang X, Yang T, Qiu Z, Zhu J, Huang J, Huang W, Feng Z; ''The role and molecular mechanism of Trop2 induced epithelial-mesenchymal transition through mediated β-catenin in gastric cancer.''; Cancer Med, 2019 PubMed Europe PMC Scholia
  8. Sin STK, Li Y, Liu M, Ma S, Guan XY; ''TROP-2 exhibits tumor suppressive functions in cervical cancer by dual inhibition of IGF-1R and ALK signaling.''; Gynecol Oncol, 2019 PubMed Europe PMC Scholia
  9. Nakatsukasa M, Kawasaki S, Yamasaki K, Fukuoka H, Matsuda A, Tsujikawa M, Tanioka H, Nagata-Takaoka M, Hamuro J, Kinoshita S; ''Tumor-associated calcium signal transducer 2 is required for the proper subcellular localization of claudin 1 and 7: implications in the pathogenesis of gelatinous drop-like corneal dystrophy.''; Am J Pathol, 2010 PubMed Europe PMC Scholia
  10. Sun X, Jia L, Wang T, Zhang Y, Zhao W, Wang X, Chen H; ''Trop2 binding IGF2R induces gefitinib resistance in NSCLC by remodeling the tumor microenvironment.''; J Cancer, 2021 PubMed Europe PMC Scholia
  11. Lin JC, Wu YY, Wu JY, Lin TC, Wu CT, Chang YL, Jou YS, Hong TM, Yang PC; ''TROP2 is epigenetically inactivated and modulates IGF-1R signalling in lung adenocarcinoma.''; EMBO Mol Med, 2012 PubMed Europe PMC Scholia
  12. Trerotola M, Li J, Alberti S, Languino LR; ''Trop-2 inhibits prostate cancer cell adhesion to fibronectin through the β1 integrin-RACK1 axis.''; J Cell Physiol, 2012 PubMed Europe PMC Scholia
  13. Stoyanova T, Goldstein AS, Cai H, Drake JM, Huang J, Witte ON; ''Regulated proteolysis of Trop2 drives epithelial hyperplasia and stem cell self-renewal via β-catenin signaling.''; Genes Dev, 2012 PubMed Europe PMC Scholia
  14. Hou J, Lv A, Deng Q, Zhang G, Hu X, Cui H; ''TROP2 promotes the proliferation and metastasis of glioblastoma cells by activating the JAK2/STAT3 signaling pathway.''; Oncol Rep, 2019 PubMed Europe PMC Scholia
  15. Ju X, Jiao X, Ertel A, Casimiro MC, Di Sante G, Deng S, Li Z, Di Rocco A, Zhan T, Hawkins A, Stoyanova T, Andò S, Fatatis A, Lisanti MP, Gomella LG, Languino LR, Pestell RG; ''v-Src Oncogene Induces Trop2 Proteolytic Activation via Cyclin D1.''; Cancer Res, 2016 PubMed Europe PMC Scholia
  16. Gao XY, Zhu YH, Zhang LX, Lu HY, Jiang AG; ''siRNA targeting of Trop2 suppresses the proliferation and invasion of lung adenocarcinoma H460 cells.''; Exp Ther Med, 2015 PubMed Europe PMC Scholia
  17. 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; ''Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer.''; Neoplasia, 2021 PubMed Europe PMC Scholia
  18. Wu B, Yu C, Zhou B, Huang T, Gao L, Liu T, Yang X; ''Overexpression of TROP2 promotes proliferation and invasion of ovarian cancer cells.''; Exp Ther Med, 2017 PubMed Europe PMC Scholia
  19. Guerra E, Trerotola M, Aloisi AL, Tripaldi R, Vacca G, La Sorda R, Lattanzio R, Piantelli M, Alberti S; ''The Trop-2 signalling network in cancer growth.''; Oncogene, 2013 PubMed Europe PMC Scholia
  20. Yang J, Zhu Z, Wang H, Li F, Du X, Ma RZ; ''Trop2 regulates the proliferation and differentiation of murine compact-bone derived MSCs.''; Int J Oncol, 2013 PubMed Europe PMC Scholia
  21. Guo X, Zhu X, Zhao L, Li X, Cheng D, Feng K; ''Tumor-associated calcium signal transducer 2 regulates neovascularization of non-small-cell lung cancer via activating ERK1/2 signaling pathway.''; Tumour Biol, 2017 PubMed Europe PMC Scholia
  22. Kuai X, Jia L, Yang T, Huang X, Zhao W, Zhang M, Chen Y, Zhu J, Feng Z, Tang Q; ''Trop2 Promotes Multidrug Resistance by Regulating Notch1 Signaling Pathway in Gastric Cancer Cells.''; Med Sci Monit, 2020 PubMed Europe PMC Scholia
  23. Zhao W, Kuai X, Zhou X, Jia L, Wang J, Yang X, Tian Z, Wang X, Lv Q, Wang B, Zhao Y, Huang W; ''Trop2 is a potential biomarker for the promotion of EMT in human breast cancer.''; Oncol Rep, 2018 PubMed Europe PMC Scholia
  24. Jia L, Wang T, Ding G, Kuai X, Wang X, Wang B, Zhao W, Zhao Y; ''Trop2 inhibition of P16 expression and the cell cycle promotes intracellular calcium release in OSCC.''; Int J Biol Macromol, 2020 PubMed Europe PMC Scholia
  25. 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; ''Trop-2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis.''; Neoplasia, 2021 PubMed Europe PMC Scholia
  26. Gu QZ, Nijiati A, Gao X, Tao KL, Li CD, Fan XP, Tian Z; ''TROP2 promotes cell proliferation and migration in osteosarcoma through PI3K/AKT signaling.''; Mol Med Rep, 2018 PubMed Europe PMC Scholia
  27. Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Arrojo R, Liu D, Rossi EA, Chang CH, Goldenberg DM; ''Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers.''; Bioconjug Chem, 2015 PubMed Europe PMC Scholia
  28. Tang G, Tang Q, Jia L, Chen Y, Lin L, Kuai X, Gong A, Feng Z; ''TROP2 increases growth and metastasis of human oral squamous cell carcinoma through activation of the PI3K/Akt signaling pathway.''; Int J Mol Med, 2019 PubMed Europe PMC Scholia
  29. Sun X, Xing G, Zhang C, Lu K, Wang Y, He X; ''Knockdown of Trop2 inhibits proliferation and migration and induces apoptosis of endometrial cancer cells via AKT/β-catenin pathway.''; Cell Biochem Funct, 2020 PubMed Europe PMC Scholia
  30. Sun H, Chen Q, Liu W, Liu Y, Ruan S, Zhu C, Ruan Y, Ying S, Lin P; ''TROP2 modulates the progression in papillary thyroid carcinoma.''; J Cancer, 2021 PubMed Europe PMC Scholia
  31. Liu X, Li S, Yi F; ''Trop2 gene: a novel target for cervical cancer treatment.''; J Cancer Res Clin Oncol, 2014 PubMed Europe PMC Scholia
  32. McDougall AR, Hooper SB, Zahra VA, Cole TJ, Lo CY, Doran T, Wallace MJ; ''Trop2 regulates motility and lamellipodia formation in cultured fetal lung fibroblasts.''; Am J Physiol Lung Cell Mol Physiol, 2013 PubMed Europe PMC Scholia
  33. Sawanyawisuth K, Tantapotinan N, Wongkham C, Riggins GJ, Kraiklang R, Wongkham S, Puapairoj A; ''Suppression of trophoblast cell surface antigen 2 enhances proliferation and migration in liver fluke-associated cholangiocarcinoma.''; Ann Hepatol, 2016 PubMed Europe PMC Scholia
  34. 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; ''Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1.''; Proc Natl Acad Sci U S A, 2020 PubMed Europe PMC Scholia
  35. Pavši� M; ''Trop2 Forms a Stable Dimer with Significant Structural Differences within the Membrane-Distal Region as Compared to EpCAM.''; Int J Mol Sci, 2021 PubMed Europe PMC Scholia
  36. Cubas R, Zhang S, Li M, Chen C, Yao Q; ''Trop2 expression contributes to tumor pathogenesis by activating the ERK MAPK pathway.''; Mol Cancer, 2010 PubMed Europe PMC Scholia
  37. Kamble PR, Rane S, Breed AA, Joseph S, Mahale SD, Pathak BR; ''Proteolytic cleavage of Trop2 at Arg87 is mediated by matriptase and regulated by Val194.''; FEBS Lett, 2020 PubMed Europe PMC Scholia
  38. Zimmers SM, Browne EP, Williams KE, Jawale RM, Otis CN, Schneider SS, Arcaro KF; ''TROP2 methylation and expression in tamoxifen-resistant breast cancer.''; Cancer Cell Int, 2018 PubMed Europe PMC Scholia
  39. Li X, Teng S, Zhang Y, Zhang W, Zhang X, Xu K, Yao H, Yao J, Wang H, Liang X, Hu Z; ''TROP2 promotes proliferation, migration and metastasis of gallbladder cancer cells by regulating PI3K/AKT pathway and inducing EMT.''; Oncotarget, 2017 PubMed Europe PMC Scholia
  40. 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; ''Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors.''; Clin Cancer Res, 2016 PubMed Europe PMC Scholia
  41. Guan H, Guo Z, Liang W, Li H, Wei G, Xu L, Xiao H, Li Y; ''Trop2 enhances invasion of thyroid cancer by inducing MMP2 through ERK and JNK pathways.''; BMC Cancer, 2017 PubMed Europe PMC Scholia


124970view20:26, 10 January 2023KhanspersOntology Term : 'signaling pathway' added !
124847view21:13, 14 December 2022EweitzModified title
124560view00:44, 9 November 2022EweitzModified title
124536view08:11, 7 November 2022Rex D A BNew pathway

External references


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NameTypeDatabase referenceComment
ABCC1Protein4363 (Entrez Gene)
ACVRL1Protein94 (Entrez Gene)
ADAM10 Protein102 (Entrez Gene)
ADAM17 Protein6868 (Entrez Gene)
AKT1Protein4070 (Entrez Gene)
AP1Protein4070 (Entrez Gene)
ARProtein9076 (Entrez Gene)
BAXProtein581 (Entrez Gene)
BCL2Protein596 (Entrez Gene)
CASP3Protein9076 (Entrez Gene)
CCND1Protein595 (Entrez Gene)
CCNE1Protein898 (Entrez Gene)
CD56Protein9076 (Entrez Gene)
CDH1Protein999 (Entrez Gene)
CDK2Protein1017 (Entrez Gene)
CDK4Protein1019 (Entrez Gene)
CDKN1BProtein1027 (Entrez Gene)
CDKN2AProtein1029 (Entrez Gene)
CLDN1Protein9076 (Entrez Gene)
CLDN7Protein1366 (Entrez Gene)
CREB1Protein3725 (Entrez Gene)
CTNNB1Protein1499 (Entrez Gene)
EGFRProtein1956 (Entrez Gene)
FN1Protein2335 (Entrez Gene)
IGF1Protein3479 (Entrez Gene)
IGF1RProtein3480 (Entrez Gene)
IGF2Protein3481 (Entrez Gene)
IGF2RProtein3482 (Entrez Gene)
ITGA5Protein3678 (Entrez Gene)
ITGB1Protein3688 (Entrez Gene)
JAK2GeneProduct3717 (Entrez Gene)
JUNProtein3725 (Entrez Gene)
MAPK1Protein9076 (Entrez Gene)
MAPK3Protein9076 (Entrez Gene)
MAPK8Protein9076 (Entrez Gene)
MAPK9Protein9076 (Entrez Gene)
MDKProtein4192 (Entrez Gene)
MMP13Protein4322 (Entrez Gene)
MMP2Protein1111 (Entrez Gene)
MYCProtein9076 (Entrez Gene)
NFKB1Protein4790 (Entrez Gene)
NOTCH1Protein4851 (Entrez Gene)
NUMBRna8650 (Entrez Gene)
OCT3/4Protein9076 (Entrez Gene)
PAK4Protein10298 (Entrez Gene)
PARP1Protein9076 (Entrez Gene)
PDPK1Protein4070 (Entrez Gene)
PECAM1Protein5175 (Entrez Gene)
PIK3R1Protein5295 (Entrez Gene)
PRKAA2Protein4851 (Entrez Gene)
PRKCAProtein5578 (Entrez Gene)
PRKCDProtein5580 (Entrez Gene)
PSAProtein9076 (Entrez Gene)
PSEN1 Protein5663 (Entrez Gene)
PSEN2Protein5664 (Entrez Gene)
PSMAProtein9076 (Entrez Gene)
PTENProtein5728 (Entrez Gene)
PTK2Protein5747 (Entrez Gene)
RAC1Protein5879 (Entrez Gene)
RACK1Protein10399 (Entrez Gene)
RB1Protein5925 (Entrez Gene)
SOX2Protein9076 (Entrez Gene)
SRCProtein6714 (Entrez Gene)
STAT1Protein6772 (Entrez Gene)
STAT3Protein9076 (Entrez Gene)
SYPProtein9076 (Entrez Gene)
TACSTD2Protein4070 (Entrez Gene)
TLN1Protein7094 (Entrez Gene)
TP63Protein9076 (Entrez Gene)
VIMProtein7431 (Entrez Gene)

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