title: The LRRK2-related Roco kinase Roco2 is regulated by Rab1A and controls the actin cytoskeleton.
abstract: We identify a new pathway that is required for proper pseudopod formation. We show that Roco2, a leucine-rich repeat kinase 2 (LRRK2)-related Roco kinase, is activated in response to chemoattractant stimulation and helps mediate cell polarization and chemotaxis by regulating cortical F-actin polymerization and pseudopod extension in a pathway that requires Rab1A. We found that Roco2 binds the small GTPase Rab1A as well as the F-actin cross-linking protein filamin (actin-binding protein 120, abp120) in vivo. We show that active Rab1A (Rab1A-GTP) is required for and regulates Roco2 kinase activity in vivo and that filamin lies downstream from Roco2 and controls pseudopod extension during chemotaxis and random cell motility. Therefore our study uncovered a new signaling pathway that involves Rab1A and controls the actin cytoskeleton and pseudopod extension, and thereby, cell polarity and motility. These findings also may have implications in the regulation of other Roco kinases, including possibly LRRK2, in metazoans.
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0380, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kicka
authors.forename: Zhouxin
authors.initials: Z
authors.lastname: Shen
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Annesley
authors.forename: Paul R
authors.initials: PR
authors.lastname: Fisher
authors.forename: Susan
authors.initials: S
authors.lastname: Lee
authors.forename: Steven
authors.initials: S
authors.lastname: Briggs
authors.forename: Richard A
authors.initials: RA
authors.lastname: Firtel
mesh_terms: D000199:Actins / Q000378:metabolism*; D016764:Cell Polarity / Q000502:physiology; D002630:Chemotactic Factors / Q000378:metabolism; D002633:Chemotaxis / Q000502:physiology; D003285:Contractile Proteins / Q000378:metabolism; D004023:Dictyostelium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D064448:Filamins; D000090263:Leucine-Rich Repeat Proteins; D008840:Microfilament Proteins / Q000378:metabolism; D058105:Polymerization; D011485:Protein Binding / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D015800:Protozoan Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020761:rab1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000199:Actins; D002630:Chemotactic Factors; D003285:Contractile Proteins; D064448:Filamins; D000090263:Leucine-Rich Repeat Proteins; D008840:Microfilament Proteins; D011506:Proteins; D015800:Protozoan Proteins; D011494:Protein Kinases; D020761:rab1 GTP-Binding Proteins