title: Leupaxin stimulates adhesion and migration of prostate cancer cells through modulation of the phosphorylation status of the actin-binding protein caldesmon.
abstract: The focal adhesion protein leupaxin (LPXN) is overexpressed in a subset of prostate cancers (PCa) and is involved in the progression of PCa. In the present study, we analyzed the LPXN-mediated adhesive and cytoskeletal changes during PCa progression. We identified an interaction between the actin-binding protein caldesmon (CaD) and LPXN and this interaction is increased during PCa cell migration. Furthermore, knockdown of LPXN did not affect CaD expression but reduced CaD phosphorylation. This is known to destabilize the affinity of CaD to F-actin, leading to dynamic cell structures that enable cell motility. Thus, downregulation of CaD increased migration and invasion of PCa cells. To identify the kinase responsible for the LPXN-mediated phosphorylation of CaD, we used data from an antibody array, which showed decreased expression of TGF-beta-activated kinase 1 (TAK1) after LPXN knockdown in PC-3 PCa cells. Subsequent analyses of the downstream kinases revealed the extracellular signal-regulated kinase (ERK) as an interaction partner of LPXN that facilitates CaD phosphorylation during LPXN-mediated PCa cell migration. In conclusion, we demonstrate that LPXN directly influences cytoskeletal dynamics via interaction with the actin-binding protein CaD and regulates CaD phosphorylation by recruiting ERK to highly dynamic structures within PCa cells.
authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Dierks
authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Germany.|Center of Pharmacology and Toxicology, Hannover Medical School, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: von Hardenberg
authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Germany.|Department of Anatomy, University of Witten/Herdecke, Witten, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Bremmer
authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Burfeind
authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Kaulfuß
mesh_terms: D000199:Actins / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D000199:Actins; D002148:Calmodulin-Binding Proteins; D015815:Cell Adhesion Molecules; C112251:LPXN protein, human; D010750:Phosphoproteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: caldesmon; leupaxin; migration; prostate cancer