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Metastatic tumor cells induce a crosstalk between endothelial p38 and ERK1/2 MAPK pathways activating endothelial MMP system (LB838)
Author(s) -
Glinskii Olga,
Glinsky Vladislav
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.lb838
Subject(s) - crosstalk , rhoa , microbiology and biotechnology , p38 mitogen activated protein kinases , dephosphorylation , extravasation , mapk/erk pathway , chemistry , kinase , matrix metalloproteinase , cancer research , signal transduction , phosphatase , phosphorylation , biology , immunology , biochemistry , physics , optics
Our recent results demonstrate that metastatic cell adhesive interactions with endothelial cells (EC) are stabilized by the endothelial integrin α3β1 leading to the activation of p38 and ERK1/2 pathways in endothelial cells when they interact with tumor cells. Here we demonstrate that, while FAK/Src/RhoA/ROCK/MKK3/6/p38 pathway is fully activated downstream of α3β1 in EC, endothelial ERK1/2 is progressively dephosphorylated despite time‐dependent MEK1/2 activation. We further demonstrate that ERK1/2 dephosphorylation results from a crosstalk between p38 and ERK1/2 pathways whereby p38‐dependent increase in the expression of dual specificity phosphatase MKP‐3 causes progressive ERK1/2 deactivation. The resulting outcome of this complex crosstalk between the two major endothelial MAP kinases is p38‐dependent activation of MT1‐MMP, increase in MMP‐9 expression, and progressive release of MMP‐2 from ECs. We conclude that upon interaction with ECs, metastatic cells highjack EC MMP system via α3β1‐induced crosstalk between major MAPK pathways to facilitate tumor cell extravasation. Grant Funding Source : Supported by the VA BLR&D Service Award 1I01BX000609 and NIH Grant R01CA160461 to VV Glinsky