title: The RalB small GTPase mediates formation of invadopodia through a GTPase-activating protein-independent function of the RalBP1/RLIP76 effector.
abstract: Our recent studies implicated key and distinct roles for the highly related RalA and RalB small GTPases (82% sequence identity) in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and invasive and metastatic growth, respectively. How RalB may promote PDAC invasion and metastasis has not been determined. In light of known Ral effector functions in regulation of actin organization and secretion, we addressed a possible role for RalB in formation of invadopodia, actin-rich membrane protrusions that contribute to tissue invasion and matrix remodeling. We determined that a majority of KRAS mutant PDAC cell lines exhibited invadopodia and that expression of activated K-Ras is both necessary and sufficient for invadopodium formation. Invadopodium formation was not dependent on the canonical Raf-MEK-ERK effector pathway and was instead dependent on the Ral effector pathway. However, this process was more dependent on RalB than on RalA. Surprisingly, RalB-mediated invadopodium formation was dependent on RalBP1/RLIP76 but not Sec5 and Exo84 exocyst effector function. Unexpectedly, the requirement for RalBP1 was independent of its best known function as a GTPase-activating protein for Rho small GTPases. Instead, disruption of the ATPase function of RalBP1 impaired invadopodium formation. Our results identify a novel RalB-mediated biochemical and signaling mechanism for invadopodium formation.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Neel
authors.forename: Kent L
authors.initials: KL
authors.lastname: Rossman
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Martin
authors.forename: Tikvah K
authors.initials: TK
authors.lastname: Hayes
authors.forename: Jen Jen
authors.initials: JJ
authors.lastname: Yeh
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Der
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology; D045744:Cell Line, Tumor; D022081:Cell Surface Extensions / Q000201:enzymology* / Q000648:ultrastructure; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness / Q000648:ultrastructure; D010190:Pancreatic Neoplasms / Q000473:pathology; D015398:Signal Transduction; D020725:ral GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D020690:GTPase-Activating Proteins; C095637:RALBP1 protein, human; C483163:Ralb protein, human; D020725:ral GTP-Binding Proteins