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UCSC Genome Browser Gene Interaction Graph
Gene interactions and pathways from curated databases and text-mining
Int J Cancer 2004, PMID: 15197768

Signaling pathways required for matrix metalloproteinase-9 induction by betacellulin in head-and-neck squamous carcinoma cells.

O-charoenrat, Pornchai; Wongkajornsilp, Adisak; Rhys-Evans, Peter H; Eccles, Suzanne A

The mechanisms by which c-erbB-dependent signaling contribute to the invasive potential of HNSCC remain to be fully elucidated. We have previously shown that c-erbB autocrine and/or paracrine stimulation upregulates MMP-9 but has no effect on the related gelatinase, MMP-2. BTC, a major c-erbB ligand, has the ability to efficiently activate all c-erbB receptors and to bind directly to EGFR and c-erbB-4. BTC is commonly expressed in HNSCC cells and exerts the most potent effects in terms of MMP induction relative to other c-erbB ligands so far tested. In the present study, we explored the contribution of major downstream events triggered by BTC/c-erbB receptor signaling to the regulation of MMP-9 and in vitro invasiveness of HNSCC cells. In human HNSCC cell lines, SIHN-006 and Detroit-562, BTC treatment resulted in rapid tyrosine phosphorylation of all c-erbB receptors whereas both endogenous MMP-9 and BTC-stimulated MMP-9 were predominantly mediated via EGFR. BTC induced ERK1/2, JNK/SAPK and Akt phosphorylation with differing kinetics but not p38 kinase. The BTC-dependent activation of JNK and PI3K/Akt pathways occurred predominantly via EGFR, whereas activation of the MEK-1/ERK pathway occurred via all 4 c-erbB receptors, although again predominantly via EGFR. Selective inhibition of ERK/MAPK (by PD98059 or U0126) and PI3K (by LY294002 or wortmannin) led to marked reduction of both basal and BTC-induced MMP-9 activity and invasive ability of HNSCC cells. In contrast, inhibition of p38 kinase with SB203580 produced no such effects. A specific inhibitor of NF-kappa B, BAY 11-7085, also blocked the stimulatory effect of BTC. No remarkable inhibition of MMP-9 and invasion was observed on targeting other cellular activities, such as PKA, PKC and PLC-gamma. Taken together, our data show that BTC induces MMP-9 production and invasion primarily through activation of EGFR, MAPK and PI3K/Akt in HNSCC cells.

Diseases/Pathways annotated by Medline MESH: Carcinoma, Squamous Cell, Head and Neck Neoplasms
Document information provided by NCBI PubMed

Text Mining Data

MMP-9 → BTC: " In human HNSCC cell lines, SIHN-006 and Detroit-562, BTC treatment resulted in rapid tyrosine phosphorylation of all c-erbB receptors whereas both endogenous MMP-9 and BTC stimulated MMP-9 were predominantly mediated via EGFR "

BTC → ERK1/2: " BTC induced ERK1/2 , JNK/SAPK and Akt phosphorylation with differing kinetics but not p38 kinase "

BTC → Akt: " BTC induced ERK1/2, JNK/SAPK and Akt phosphorylation with differing kinetics but not p38 kinase "

MMP-9 → BTC: " Selective inhibition of ERK/MAPK ( by PD98059 or U0126 ) and PI3K ( by LY294002 or wortmannin ) led to marked reduction of both basal and BTC induced MMP-9 activity and invasive ability of HNSCC cells "

MMP-9 → ERK/MAPK: " Selective inhibition of ERK/MAPK ( by PD98059 or U0126 ) and PI3K ( by LY294002 or wortmannin ) led to marked reduction of both basal and BTC induced MMP-9 activity and invasive ability of HNSCC cells "

MMP-9 → ERK/MAPK: " Selective inhibition of ERK/MAPK ( by PD98059 or U0126 ) and PI3K ( by LY294002 or wortmannin ) led to marked reduction of both basal and BTC induced MMP-9 activity and invasive ability of HNSCC cells "

MMP-9 → PI3K: " Selective inhibition of ERK/MAPK ( by PD98059 or U0126 ) and PI3K ( by LY294002 or wortmannin ) led to marked reduction of both basal and BTC induced MMP-9 activity and invasive ability of HNSCC cells "

BTC → MMP-9: " Taken together, our data show that BTC induces MMP-9 production and invasion primarily through activation of EGFR, MAPK and PI3K/Akt in HNSCC cells "

MAPK → BTC: " Taken together, our data show that BTC induces MMP-9 production and invasion primarily through activation of EGFR, MAPK and PI3K/Akt in HNSCC cells "

MAPK → MMP-9: " Taken together, our data show that BTC induces MMP-9 production and invasion primarily through activation of EGFR, MAPK and PI3K/Akt in HNSCC cells "

EGFR → BTC: " Taken together, our data show that BTC induces MMP-9 production and invasion primarily through activation of EGFR , MAPK and PI3K/Akt in HNSCC cells "

EGFR → MMP-9: " Taken together, our data show that BTC induces MMP-9 production and invasion primarily through activation of EGFR , MAPK and PI3K/Akt in HNSCC cells "

PI3K/Akt → BTC: " Taken together, our data show that BTC induces MMP-9 production and invasion primarily through activation of EGFR, MAPK and PI3K/Akt in HNSCC cells "

PI3K/Akt → MMP-9: " Taken together, our data show that BTC induces MMP-9 production and invasion primarily through activation of EGFR, MAPK and PI3K/Akt in HNSCC cells "

PI3K/Akt → BTC: " Taken together, our data show that BTC induces MMP-9 production and invasion primarily through activation of EGFR, MAPK and PI3K/Akt in HNSCC cells "

PI3K/Akt → MMP-9: " Taken together, our data show that BTC induces MMP-9 production and invasion primarily through activation of EGFR, MAPK and PI3K/Akt in HNSCC cells "

Manually curated Databases

No curated data.