title: PTPRN2 and PLCβ1 promote metastatic breast cancer cell migration through PI(4,5)P2-dependent actin remodeling.
abstract: Altered abundance of phosphatidyl inositides (PIs) is a feature of cancer. Various PIs mark the identity of diverse membranes in normal and malignant cells. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) resides predominantly in the plasma membrane, where it regulates cellular processes by recruiting, activating, or inhibiting proteins at the plasma membrane. We find that PTPRN2 and PLCβ1 enzymatically reduce plasma membrane PI(4,5)P2 levels in metastatic breast cancer cells through two independent mechanisms. These genes are upregulated in highly metastatic breast cancer cells, and their increased expression associates with human metastatic relapse. Reduction in plasma membrane PI(4,5)P2 abundance by these enzymes releases the PI(4,5)P2-binding protein cofilin from its inactive membrane-associated state into the cytoplasm where it mediates actin turnover dynamics, thereby enhancing cellular migration and metastatic capacity. Our findings reveal an enzymatic network that regulates metastatic cell migration through lipid-dependent sequestration of an actin-remodeling factor.
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY, USA.
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: Sengelaub
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Navrazhina
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY, USA.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Ross
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY, USA.
authors.forename: Nils
authors.initials: N
authors.lastname: Halberg
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY, USA stavazoie@rockefeller.edu.
authors.forename: Sohail F
authors.initials: SF
authors.lastname: Tavazoie
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002465:Cell Movement; D006801:Humans; D016513:Mice, SCID; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D054799:Phospholipase C beta / Q000378:metabolism*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D019269:Phosphatidylinositol 4,5-Diphosphate; C102889:PTPRN2 protein, human; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; C518033:PLCB1 protein, human; D054799:Phospholipase C beta
keywords: PI(4,5)P2; actin; metastasis; phosphoinositides; tumor migration