Intracellular targeting of annexin A2 inhibits tumor cell adhesion, migration, and in vivo grafting

Cytoskeletal-associated proteins play an active role in coordinating the adhesion and migration machinery in cancer progression. To identify functional protein networks and potential inhibitors, we screened an internalizing phage (iPhage) display library in tumor cells, and selected LGRFYAASG as a cytosol-targeting peptide. By affinity purification and mass spectrometry, intracellular annexin A2 was identified as the corresponding binding protein. Consistently, annexin A2 and a cell-internalizing, penetratin-fused version of the selected peptide (LGRFYAASG-pen) co-localized and specifically accumulated in the cytoplasm at the cell edges and cell-cell contacts. Functionally, tumor cells incubated with LGRFYAASG-pen showed disruption of filamentous actin, focal adhesions and caveolae-mediated membrane trafficking, resulting in impaired cell adhesion and migration in vitro. These effects were paralleled by a decrease in the phosphorylation of both focal adhesion kinase (Fak) and protein kinase B (Akt). Likewise, tumor cells pretreated with LGRFYAASG-pen exhibited an impaired capacity to colonize the lungs in vivo in several mouse models. Together, our findings demonstrate an unrecognized functional link between intracellular annexin A2 and tumor cell adhesion, migration and in vivo grafting. Moreover, this work uncovers a new peptide motif that binds to and inhibits intracellular annexin A2 as a candidate therapeutic lead for potential translation into clinical applications

The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease

Fil: El-Sayed, Najib M. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Myler, Peter J. Seattle Biomedical Research Institute; Estados Unidos.Fil: Bartholomeu, Daniella C. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Nilsson, Daniel. Karolinska Institutet. Center for Genomics and Bioinformatics; Suecia.Fil: Aggarwal, Gautam. Seattle Biomedical Research Institute; Estados Unidos.Fil: Tran, Anh-Nhi. Karolinska Institutet. Center for Genomics and Bioinformatics; Suecia.Fil: Ghedin, Elodie. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Worthey, Elizabeth A. Seattle Biomedical Research Institute; Estados Unidos.Fil: Delcher, Arthur L. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Blandin, Gaëlle. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Westenberger, Scott J. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Caler, Elisabet. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Cerqueira, Gustavo C. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Haas, Carole Branched Brian. Karolinska Institutet. Center for Genomics and Bioinformatics; Suecia.Fil: Anupama, Atashi. Seattle Biomedical Research Institute; Estados Unidos.Fil: Arner, Erik. Karolinska Institutet. Center for Genomics and Bioinformatics; Suecia.Fil: Åslund, Lena. Uppsala University. Department of Genetics and Pathology; Suecia.Fil: Attipoe, Philip. Seattle Biomedical Research Institute; Estados Unidos.Fil: Bontempi, Esteban. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Bringaud, Frédéric. Université Victor Segalen Bordeaux II. Laboratoire de Génomique Fonctionnelle des Trypanosomatides; Francia.Fil: Burton, Peter. University of Glasgow. Wellcome Centre for Molecular Parasitology; Reino Unido.Fil: Cadag, Eithon. Seattle Biomedical Research Institute; Estados Unidos.Fil: Campbell, David A. University of California. Department of Microbiology; Estados Unidos.Fil: Carrington, Mark. University of Cambridge. Department of Biochemistry; Reino Unido.Fil: Crabtree, Jonathan. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Darban, Hamid. Karolinska Institutet. Center for Genomics and Bioinformatics; Suecia.Fil: Silveira, Jose Franco da. Universidade Federal de Sao Paulo. Departamento de Microbiologia; Brasil.Fil: Jong, Pieter de. Children’s Hospital Oakland Research Institute. BACPAC Resources; Estados Unidos.Fil: Edwards, Kimberly. Karolinska Institutet. Center for Genomics and Bioinformatics; Suecia.Fil: Englund, Paul T. Johns Hopkins University School of Medicine. Department of Biological Chemistry; Estados Unidos.Fil: Fazelina, Gholam. Seattle Biomedical Research Institute; Estados Unidos.Fil: Feldblyum, Tamara. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Ferella, Marcela. Karolinska Institutet. Center for Genomics and Bioinformatics; Suecia.Fil: Frasch, Alberto Carlos. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina.Fil: Gull, Keith. University of Oxford. Sir William Dunn School of Pathology; Reino Unido.Fil: Horn, David. London School of Hygiene and Tropical Medicine; Reino Unido.Fil: Hou, Lihua. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Huang, Yiting. Seattle Biomedical Research Institute; Estados Unidos.Fil: Kindlund, Ellen. Karolinska Institutet. Center for Genomics and Bioinformatics; Suecia.Fil: Klingbeil, Michele. University of Massachusetts. Department of Microbiology; Estados Unidos.Fil: Kluge, Sindy. Karolinska Institutet. Center for Genomics and Bioinformatics; Suecia.Fil: Koo, Hean. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Lacerda, Daniela. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Levin, Mariano J. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET-CYTED project). Laboratorio de Biología Molecular de la Enfermedad de Chagas; Argentina.Fil: Lorenzi, Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET-CYTED project). Laboratorio de Biología Molecular de la Enfermedad de Chagas; Argentina.Fil: Louie, Tin. Seattle Biomedical Research Institute; Estados Unidos.Fil: Machado, Carlos Renato. Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia; Brasil.Fil: McCulloch, Richard. University of Glasgow. Wellcome Centre for Molecular Parasitology; Reino Unido.Fil: McKenna, Alan. Karolinska Institutet. Center for Genomics and Bioinformatics; Suecia.Fil: Mizuno, Yumi. Karolinska Institutet. Center for Genomics and Bioinformatics; Suecia.Fil: Mottram, Jeremy C. University of Glasgow. Wellcome Centre for Molecular Parasitology; Reino Unido.Fil: Nelson, Siri. Seattle Biomedical Research Institute; Estados Unidos.Fil: Ochaya, Stephen. Karolinska Institutet. Center for Genomics and Bioinformatics; Suecia.Fil: Osoegawa, Kazutoyo. Children’s Hospital Oakland Research Institute. BACPAC Resources; Estados Unidos.Fil: Pai, Grace. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Parsons, Marilyn. Seattle Biomedical Research Institute; Estados Unidos.Fil: Pentony, Martin. Seattle Biomedical Research Institute; Estados Unidos.Fil: Pettersson, Ulf. Uppsala University. Department of Genetics and Pathology; Suecia.Fil: Pop, Mihai. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Ramirez, Jose Luis. Universidad Central de Venezuela. Instituto de Biología Experimental; Venezuela.Fil: Rinta, Joel. Seattle Biomedical Research Institute; Estados Unidos.Fil: Robertson, Laura. Seattle Biomedical Research Institute; Estados Unidos.Fil: Salzberg, Steven L. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Sanchez, Daniel O. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina.Fil: Seyler, Amber. Seattle Biomedical Research Institute; Estados Unidos.Fil: Sharma, Reuben. University of Cambridge. Department of Biochemistry; Reino Unido.Fil: Shetty, Jyoti. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Simpson, Anjana J. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Sisk, Ellen. Seattle Biomedical Research Institute; Estados Unidos.Fil: Tammi, Martti T. Karolinska Institutet. Center for Genomics and Bioinformatics; Suecia.Fil: Tarleton, Rick. University of Georgia. Center for Tropical and Emerging Global Diseases; Estados Unidos.Fil: Teixeira, Santuza. Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia; Brasil.Fil: Aken, Susan Van. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Vogt, Christy. Seattle Biomedical Research Institute; Estados Unidos.Fil: Ward, Pauline N. University of Glasgow. Wellcome Centre for Molecular Parasitology; Reino Unido.Fil: Wickstead, Bill. University of Oxford. Sir William Dunn School of Pathology; Reino Unido.Fil: Wortman, Jennifer. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: White, Owen. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Fraser, Claire M. The Institute for Genomic Research. Department of Parasite Genomics; Estados Unidos.Fil: Stuart, Kenneth D. Seattle Biomedical Research Institute; Estados Unidos.Fil: Andersson, Björn. Karolinska Institutet. Center for Genomics and Bioinformatics; Suecia.Whole-genome sequencing of the protozoan pathogen Trypanosoma cruzi revealed that the diploid genome contains a predicted 22,570 proteins encoded by genes, of which 12,570 represent allelic pairs. Over 50% of the genome consists of repeated sequences, such as retrotransposons and genes for large families of surface molecules, which include trans-sialidases, mucins, gp63s, and a large novel family (>1300 copies) of mucin-associated surface protein (MASP) genes. Analyses of the T. cruzi, T. brucei, and Leishmania major (Tritryp) genomes imply differences from other eukaryotes in DNA repair and initiation of replication and reflect their unusual mitochondrial DNA. Although the Tritryp lack several classes of signaling molecules, their kinomes contain a large and diverse set of protein kinases and phosphatases; their size and diversity imply previously unknown interactions and regulatory processes, which may be targets for intervention