title: Actin-associated protein palladin promotes tumor cell invasion by linking extracellular matrix degradation to cell cytoskeleton.
abstract: Basal-like breast carcinomas, characterized by unfavorable prognosis and frequent metastases, are associated with epithelial-to-mesenchymal transition. During this process, cancer cells undergo cytoskeletal reorganization and up-regulate membrane-type 1 matrix metalloproteinase (MT1-MMP; MMP14), which functions in actin-based pseudopods to drive invasion by extracellular matrix degradation. However, the mechanisms that couple matrix proteolysis to the actin cytoskeleton in cell invasion have remained unclear. On the basis of a yeast two-hybrid screen for the MT1-MMP cytoplasmic tail-binding proteins, we identify here a novel Src-regulated protein interaction between the dynamic cytoskeletal scaffold protein palladin and MT1-MMP. These proteins were coexpressed in invasive human basal-like breast carcinomas and corresponding cell lines, where they were associated in the same matrix contacting and degrading membrane complexes. The silencing and overexpression of the 90-kDa palladin isoform revealed the functional importance of the interaction with MT1-MMP in pericellular matrix degradation and mesenchymal tumor cell invasion, whereas in MT1-MMP-negative cells, palladin overexpression was insufficient for invasion. Moreover, this invasion was inhibited in a dominant-negative manner by an immunoglobulin domain-containing palladin fragment lacking the dynamic scaffold and Src-binding domains. These results identify a novel protein interaction that links matrix degradation to cytoskeletal dynamics and migration signaling in mesenchymal cell invasion.
authors.affiliation: Research Programs Unit, Genome-Scale Biology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland Department of Pathology, Haartman Institute, FIN-00014, University of Helsinki, Helsinki, Finland.
authors.forename: Pernilla
authors.initials: P
authors.lastname: von Nandelstadh
authors.affiliation: Research Programs Unit, Genome-Scale Biology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland Department of Pathology, Haartman Institute, FIN-00014, University of Helsinki, Helsinki, Finland.
authors.forename: Erika
authors.initials: E
authors.lastname: Gucciardo
authors.affiliation: Department of Pathology, Haartman Institute, FIN-00014, University of Helsinki, Helsinki, Finland Department of Pathology, HUSLAB, Helsinki University Central Hospital, FIN-00290, Helsinki, Finland.
authors.forename: Jouko
authors.initials: J
authors.lastname: Lohi
authors.affiliation: Research Programs Unit, Genome-Scale Biology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland Department of Pathology, Haartman Institute, FIN-00014, University of Helsinki, Helsinki, Finland.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Research Programs Unit, Genome-Scale Biology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland Department of Pathology, Haartman Institute, FIN-00014, University of Helsinki, Helsinki, Finland.
authors.forename: Nami
authors.initials: N
authors.lastname: Sugiyama
authors.affiliation: Department of Pathology, University of Turku and Turku University Central Hospital, FIN-20520, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Carpen
authors.affiliation: Research Programs Unit, Genome-Scale Biology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland Department of Pathology, Haartman Institute, FIN-00014, University of Helsinki, Helsinki, Finland kaisa.lehti@helsinki.fi.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Lehti
mesh_terms: D000199:Actins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D064211:Connectin / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D008840:Microfilament Proteins; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis
chemical_list: D000199:Actins; D064211:Connectin; D003598:Cytoskeletal Proteins; C577290:MYOT protein, human; D008840:Microfilament Proteins; C412722:PALLD protein, human; D010750:Phosphoproteins; D020033:Protein Isoforms; D053511:Matrix Metalloproteinase 14