title: Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis.
abstract: Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis.
authors.affiliation: Department of Anatomy and Structural Biology and Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461 brian.beaty@med.einstein.yu.edu john.condeelis@einstein.yu.edu.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Beaty
authors.affiliation: Department of Anatomy and Structural Biology and Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461.
authors.forename: Yarong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Anatomy and Structural Biology and Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461Department of Anatomy and Structural Biology and Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461.
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Bravo-Cordero
authors.affiliation: Department of Anatomy and Structural Biology and Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461Department of Anatomy and Structural Biology and Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461.
authors.forename: Ved P
authors.initials: VP
authors.lastname: Sharma
authors.affiliation: Department of Anatomy and Structural Biology and Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461.
authors.forename: Veronika
authors.initials: V
authors.lastname: Miskolci
authors.affiliation: Department of Anatomy and Structural Biology and Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461Department of Anatomy and Structural Biology and Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461.
authors.forename: Louis
authors.initials: L
authors.lastname: Hodgson
authors.affiliation: Department of Anatomy and Structural Biology and Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461Department of Anatomy and Structural Biology and Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461 brian.beaty@med.einstein.yu.edu john.condeelis@einstein.yu.edu.
authors.forename: John
authors.initials: J
authors.lastname: Condeelis
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008175:Lung Neoplasms / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000378:metabolism*; D009362:Neoplasm Metastasis; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D016608:Talin / Q000378:metabolism*; D000099149:Ezrin
chemical_list: D000199:Actins; D027682:Cation Transport Proteins; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D016608:Talin; D000099149:Ezrin; C490998:SLC9A1 protein, human; C071058:moesin; C071776:radixin