title: Adaptor protein LRAP25 mediates myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK) regulation of LIMK1 protein in lamellipodial F-actin dynamics.
abstract: Myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK) has been shown to localize to the lamella of mammalian cells through its interaction with an adaptor protein, leucine repeat adaptor protein 35a (LRAP35a), which links it with myosin 18A (MYO18A) for activation of the lamellar actomyosin network essential for cell migration. Here, we report the identification of another adaptor protein LRAP25 that mediates MRCK association with LIM kinase 1 (LIMK1). The lamellipodium-localized LRAP25-MRCK complex is essential for the regulation of local LIMK1 and its downstream F-actin regulatory factor cofilin. Functionally, inhibition of either MRCK or LRAP25 resulted in a marked suppression of LIMK1 activity and down-regulation of cofilin phosphorylation in response to aluminum fluoride induction in B16-F1 cells, which eventually resulted in deregulation of lamellipodial F-actin and reorganization of cytoskeletal structures causing defects in cell polarization and motility. These biochemical and functional characterizations thus underline the functional relevance of the LRAP25-MRCK complex in LIMK1-cofilin signaling and the importance of LRAP adaptors as key determinants of MRCK cellular localization and downstream specificities.
authors.affiliation: Institute of Molecular and Cell Biology, A-STAR, 61 Biopolis Drive, Singapore 138673 and; Department of Anatomy, National University of Singapore, Singapore 119260, Singapore.
authors.forename: Irene Cheng Jie
authors.initials: ICJ
authors.lastname: Lee
authors.affiliation: Institute of Molecular and Cell Biology, A-STAR, 61 Biopolis Drive, Singapore 138673 and; Department of Anatomy, National University of Singapore, Singapore 119260, Singapore.
authors.forename: Thomas
authors.initials: T
authors.lastname: Leung
authors.affiliation: Institute of Molecular and Cell Biology, A-STAR, 61 Biopolis Drive, Singapore 138673 and. Electronic address: kntan@imcb.a-star.edu.sg.
authors.forename: Ivan
authors.initials: I
authors.lastname: Tan
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism; D000199:Actins / Q000235:genetics / Q000378:metabolism*; D017607:Aluminum Compounds / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005459:Fluorides / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D054461:Lim Kinases / Q000096:biosynthesis* / Q000235:genetics; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D065636:Myotonin-Protein Kinase / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D017607:Aluminum Compounds; C453442:FAM89B protein, human; D046912:Multiprotein Complexes; D011991:Receptors, Virus; C105518:CDC42BPA protein, human; C532581:Cdc42bpa protein, rat; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515894:Limk1 protein, rat; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases; D005459:Fluorides; C032311:aluminum fluoride
keywords: Actin; Cell Motility; Cofilin; F-actin Dynamics; LIM Kinase; Lamellipodium; MRCK; Protein Phosphorylation; Small GTPase
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