Function of {alpha}3{beta}1-Tetraspanin Protein Complexes in Tumor Cell Invasion. Evidence for the Role of the Complexes in Production of Matrix Metalloproteinase 2 (Mmp-2)

doi:10.1083/jcb.146.6.1375

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© The Rockefeller University Press, 0021-9525/1999//1375 $5.00
The Journal of Cell Biology, Volume 146, Number 6, , 1999 1375-1389

Original Article

Function of ${alpha}$ 3β1–Tetraspanin Protein Complexes in Tumor Cell Invasion. Evidence for the Role of the Complexes in Production of Matrix Metalloproteinase 2 (Mmp-2)

Tsuyoshi Sugiura^a and Fedor Berditchevski^a

^a CRC Institute for Cancer Studies, The University of Birmingham, Edgbaston, Birmingham B15 2TA, United Kingdom
CRC Institute for Cancer Studies, The University of Birmingham, Edgbaston, Birmingham B15 2TA, United Kingdom.44-121-414-448644-121-414-7458

f.berditchevski{at}bham.ac.uk

Tumor cell migration through the three- dimensional extracellularmatrix (ECM) environment is an important part of the metastaticprocess. We have analyzed a role played by the integrin–tetraspaninprotein complexes in invasive migration by culturing MDA-MB-231cells within Matrigel. Using time-lapse video recording, wedemonstrated that the Matrigel-embedded cells remain round andexhibit only limited ability for migration by extending short,highly dynamic pseudopodia. The ${alpha}$ 3β1–tetraspanin proteincomplexes were clustered on the thin microvilli-like protrusionsextending from both the main cell body and pseudopodia. Ligationof the ${alpha}$ 3β1–tetraspanin protein complexes with monoclonalantibodies specifically stimulates production of matrix metalloproteinase2 (MMP-2) and induces formation of long invasive protrusionswithin Matrigel. Accordingly, treatment with the monoclonalantibodies to various tetraspanin proteins and to the ${alpha}$ 3 integrinsubunit increases invasive potential of the MDA-MB-231 cellsin the Matrigel-penetration assay. A specific inhibitor of phosphoinositide3-kinase (PI3K), LY294002, negated the effect of the monoclonalantibodies on the morphology of the Matrigel-embedded cellsand on production of MMP-2. Interestingly, broad-spectrum inhibitorsof protein tyrosine kinases (genistein) and protein tyrosinephosphatases (orthovanadate), and actin filament stabilizingcompound (jasplakinolide), also block protrusive activity ofthe Matrigel-embedded cells but have no effect on the productionof MMP-2. These results indicate that ${alpha}$ 3β1–tetraspaninprotein complexes may control invasive migration of tumor cellsby using at least two PI3K-dependent signaling mechanisms: throughrearrangement of the actin cytoskeleton and by modulating theMMP-2 production.

Key Words: integrin • tetraspanin • invasion • matrix metalloproteinase • signaling

1.used in this paper: ECM, extracellular matrix; MMP, matrixmetalloproteinase; PI3K, phosphoinositide 3-kinase; PtdIns,phosphatidylinositol; pTyr, phosphotyrosine; SH2, Src homology2; TIMP, tissue inhibitor of metalloproteinases

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