Molecule Information

General Information of the Molecule (ID: Mol04297)

• Name: Transmembrane protease serine 2 (TMPRSS2) ,Homo sapiens
• Synonyms: Serine protease 10
• Molecule Type: Protein
• Gene Name: TMPRSS2
• Gene ID: 7113
• Sequence:
  MALNSGSPPAIGPYYENHGYQPENPYPAQPTVVPTVYEVHPAQYYPSPVPQYAPRVLTQA
  SNPVVCTQPKSPSGTVCTSKTKKALCITLTLGTFLVGAALAAGLLWKFMGSKCSNSGIE
  C DSSGTCINPSNWCDGVSHCPGGEDENRCVRLYGPNFILQVYSSQRKSWHPVCQDDWNE
  NY GRAACRDMGYKNNFYSSQGIVDDSGSTSFMKLNTSAGNVDIYKKLYHSDACSSKAVV
  SLR CIACGVNLNSSRQSRIVGGESALPGAWPWQVSLHVQNVHVCGGSIITPEWIVTAAH
  CVEK PLNNPWHWTAFAGILRQSFMFYGAGYQVEKVISHPNYDSKTKNNDIALMKLQKPL
  TFNDL VKPVCLPNPGMMLQPEQLCWISGWGATEEKGKTSEVLNAAKVLLIETQRCNSRY
  VYDNLI TPAMICAGFLQGNVDSCQGDSGGPLVTSKNNIWWLIGDTSWGSGCAKAYRPGV
  YGNVMVF TDWIYRQMRADG
• Function: Plasma membrane-anchored serine protease that cleaves atarginine residues . Participates in proteolytic cascades of relevance forthe normal physiologic function of the prostate .Androgen-induced TMPRSS2 activates several substrates that include pro-hepatocyte growth factor/HGF, the protease activated receptor-2/F2RL1or matriptase/ST14 leading to extracellular matrix disruption andmetastasis of prostate cancer cells . In addition, activates trigeminal neurons andcontribute to both spontaneous pain and mechanical allodynia . {ECO:0000250|UniProtKB:Q9JIQ8,ECO:0000269|PubMed:15537383, ECO:0000269|PubMed:25122198,ECO:0000269|PubMed:26018085, ECO:0000269|PubMed:32703818,ECO:0000269|PubMed:35676539, ECO:0000269|PubMed:37990007,ECO:0000269|PubMed:38964328}.; Facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via two independent mechanisms,proteolytic cleavage of ACE2 receptor which promotes viral uptake, andcleavage of coronavirus spike glycoproteins which activates theglycoprotein for host cell entry . The cleavage of SARS-COV2 spike glycoprotein occursbetween the S2 and S2' site . Upon SARS-CoV-2infection, increases syncytia formation by accelerating the fusionprocess .Proteolytically cleaves and activates the spike glycoproteins of humancoronavirus 229E and human coronavirus EMC andthe fusion glycoproteins F0 of Sendai virus , humanmetapneumovirus , human parainfluenza 1, 2, 3, 4a and 4b viruses. Essential for spread and pathogenesis of influenza A virus; involved in proteolytic cleavage andactivation of hemagglutinin protein which is essential for viralinfectivity. {ECO:0000269|PubMed:21068237, ECO:0000269|PubMed:21325420,ECO:0000269|PubMed:23536651, ECO:0000269|PubMed:23966399,ECO:0000269|PubMed:24027332, ECO:0000269|PubMed:24227843,ECO:0000269|PubMed:32142651, ECO:0000269|PubMed:32404436,ECO:0000269|PubMed:32703818, ECO:0000269|PubMed:33051876,ECO:0000269|PubMed:34159616, ECO:0000269|PubMed:35676539,ECO:0000269|PubMed:37990007}.; Receptor for human coronavirus HKU1-CoV, acts synergistically with disialoside glycans to facilitate theentry of the virus. After binding to cell-surface disialoside glycans,the viral S protein interacts with the inactive form of TMPRSS2 andinhibits its protease activity. {ECO:0000269|PubMed:38964326,ECO:0000269|PubMed:38964328, ECO:0000269|PubMed:38964329}.
• Uniprot ID: TMPS2_HUMAN
• Ensembl ID: ENSG0000018401214
• HGNC ID: HGNC:11876

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Afatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [1]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Afatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SK-BR-3 cells; Pleural effusion; Homo sapiens (Human); CVCL_0033
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay; Clonogenic assay
• Mechanism Description: Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from?Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and?Artemisia argyi?emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer.?

Lapatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [1]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Lapatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SK-BR-3 cells; Pleural effusion; Homo sapiens (Human); CVCL_0033
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay; Clonogenic assay
• Mechanism Description: Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from?Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and?Artemisia argyi?emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer.?

Tucatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [1]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Tucatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SK-BR-3 cells; Pleural effusion; Homo sapiens (Human); CVCL_0033
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay; Clonogenic assay
• Mechanism Description: Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from?Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and?Artemisia argyi?emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer.?

References

• Ref 1: Artemisia argyi extracts overcome lapatinib resistance via enhancing TMPRSS2 activation in HER2-positive breast cancer. Environ Toxicol. 2024 Jun;39(6):3389-3399.