NHERF1 acts as a molecular switch to program metastatic behavior and organotropism via its PDZ domains

Rosa Angela Cardone, Maria Raffaella Greco, Mattia Capulli, Edward J. Weinman, Giovanni Busco, Antonia Bellizzi, Valeria Casavola, Ester Antelmi, Barbara Ambruosi, Maria Elena Dell'Aquila, Angelo Paradiso, Anna Teti, Nadia Rucci, Stephan Joel Reshkin

Research output: Contribution to journalArticlepeer-review

Abstract

Metastatic cells are highly plastic for differential expression of tumor phenotype hallmarks and metastatic organotropism. The signaling proteins orchestrating the shift of one cell phenotype and organ pattern to another are little known. Na+/H+ exchanger regulatory factor (NHERF1) is a molecular pathway organizer, PDZ-domain protein that recruits membrane, cytoplasmic, and cytoskeletal signaling proteins into functional complexes. To gain insight into the role of NHERF1 in metastatic progression, we stably transfected a metastatic breast cell line, MDA-MB-231, with an empty vector, with wild-type NHERF1, or with NHERF1 mutated in either the PDZ1- or PDZ2-binding domains to block their binding activities. We observed that NHERF1 differentially regulates the expression of two phenotypic programs through its PDZ domains, and these programs form the mechanistic basis for metastatic organotropism. The PDZ2 domain promotes visceral metastases via increased invadopodia-dependent invasion and anchorage-independent growth, as well as by inhibition of apoptosis, whereas the PDZ1 domain promotes bone metastases by stimulating podosome nucleation, motility, neoangiogenesis, vasculogenic mimicry, and osteoclastogenesis in the absence of increased growth or invasion. Collectively, these findings identify NHERF1 as an important signaling nexus for coordinating cell structure with metastatic behavior and identifies the "mesenchymal-to-vasculogenic" phenotypic transition as an essential step in meta-static progression.

Original languageEnglish
Pages (from-to)2028-2040
Number of pages13
JournalMolecular Biology of the Cell
Volume23
Issue number11
DOIs
Publication statusPublished - Jun 1 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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