title: Amino-terminal fragments of laminin γ2 chain stimulate migration of metastatic breast cancer cells by interacting with CD44.
abstract: Laminin γ2 (Lmγ2) chain, a subunit of the basement membrane protein laminin-332, is regarded as a typical cancer invasion marker. The overexpression of Lmγ2 chain by invasive cancer cells correlates with poor prognosis of cancer patients, and its forced expression in human cancer cells promotes their invasive growth in a nude mouse model. However, its actual roles in cancer progression, as well as the mechanism of its proinvasive effect, remain unclear. CD44 is known to be an important cancer stem cell marker and support cancer progression and stem cell functions. Here we demonstrate that amino-terminal fragments of Lmγ2 interact with CD44 on the membrane of breast cancer cells. Lmγ2 highly bound to the metastatic cell line MDA-MB-231 but poorly to the benign cell line MCF-7. The membrane receptor for Lmγ2 on MDA-MB-231 cells was identified to be the standard form of CD44 (CD44s) by co-immunoprecipitation, affinity chromatography and direct protein interaction assay. Lmγ2 interacted with CD44s through EGF-like repeat 2/3 in the Lmγ2 amino-terminus. Amino-terminal fragments of Lmγ2 induced the phosphorylation of CD44 cytoplasmic domain and stimulated migration of the cancer cells in a CD44-dependent manner. This migration was blocked by inhibitors of TGF-β receptor I (TGF-βRI) kinase. These results suggest that two important tumor markers, Lmγ2 and CD44, cooperate for cancer progression and possibly for cancer stem cell functions. TGF-βRI may be involved in the Lmγ2/CD44 interaction.
authors.affiliation: Department of Genome Science, Graduate School of Nanobioscience, Yokohama City University, 641-12 Maioka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-0813, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sato
authors.forename: Shouichi
authors.initials: S
authors.lastname: Higashi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Miyazaki
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000556:secondary*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002846:Chromatography, Affinity; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D047468:Immunoprecipitation; D007797:Laminin / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D018960:Hyaluronan Receptors; C400567:LAMC2 protein, human; D007797:Laminin; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I