title: BART inhibits pancreatic cancer cell invasion by inhibiting ARL2-mediated RhoA inactivation.
abstract: We report that BART plays a role in inhibiting cell invasion by regulating the activity of the Rho GTPase protein RhoA in pancreatic cancer cells. BART was originally identified as a binding partner of ARL2, a small G-protein implicated as a regulator of microtubule dynamics and folding. We show that BART interacts with GTP-bound ARL2 and is required for the binding of GTP-bound ARL2 with active forms of RhoA at leading edges in migrating cancer cells. GTP-bound ARL2 inactivates RhoA and BART prevents ARL2 from regulating RhoA activity. Thus, BART binds to and functions as an inhibitor of ARL2 at leading edges of migrating cells, thereby increasing the amount of active RhoA. Treatment with the Rho inhibitor C3 exoenzyme induces cell invasion by pancreatic cancer cells to the same level as that of cells in which BART is stably knocked down by RNA interference. GTP-bound ARL2 acts as a RhoA inhibitor by a mechanism that involves the induction of actin-cytoskeleton rearrangements. We show that BART decreases actin-cytoskeleton rearrangements by inhi-biting ARL2 function and by increasing the amount of active RhoA in pancreatic cancer cells. Our results imply that BART increases active RhoA by inhibiting ARL2 function, which in turn inhibits invasiveness of cancer cells.
authors.affiliation: Department of Gastro-enterology and Hepatology, Kochi University Medical School, Nankoku, Kochi 783-8505, Japan. jm-ktaniuchi@kochi-u.ac.jp
authors.forename: Keisuke
authors.initials: K
authors.lastname: Taniuchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Iwasaki
authors.forename: Toshiji
authors.initials: T
authors.lastname: Saibara
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D021381:Protein Transport; D014157:Transcription Factors; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C485676:ARL2BP protein, human; D002352:Carrier Proteins; D014157:Transcription Factors; C410130:ARL2 protein, human; D019204:GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein