title: An mDia1-INF2 formin activation cascade facilitated by IQGAP1 regulates stable microtubules in migrating cells.
abstract: Multiple formins regulate microtubule (MT) arrays, but whether they function individually or in a common pathway is unknown. Lysophosphatidic acid (LPA) stimulates the formation of stabilized detyrosinated MTs (Glu MTs) in NIH3T3 fibroblasts through RhoA and the formin mDia1. Here we show that another formin, INF2, is necessary for mDia1-mediated induction of Glu MTs and regulation of MT dynamics and that mDia1 can be bypassed by activating INF2. INF2 localized to MTs after LPA treatment in an mDia1-dependent manner, suggesting that mDia1 regulates INF2. Mutants of either formin that disrupt their interaction failed to rescue MT stability in cells depleted of the respective formin, and the mDia1-interacting protein IQGAP1 regulated INF2's localization to MTs and the induction of Glu MTs by either formin. The N-terminus of IQGAP1 associated with the C-terminus of INF2 directly, suggesting the possibility of a tripartite complex stimulated by LPA. Supporting this, the interaction of mDia1 and INF2 was induced by LPA and dependent on IQGAP1. Our data highlight a unique mechanism of formin action in which mDia1 and INF2 function in series to stabilize MTs and point to IQGAP1 as a scaffold that facilitates the activation of one formin by another.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bartolini
authors.affiliation: Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas and Universidad Autonoma de Madrid, 28049 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Andres-Delgado
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Qu
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032.
authors.forename: Sara
authors.initials: S
authors.lastname: Nik
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032.
authors.forename: Nagendran
authors.initials: N
authors.lastname: Ramalingam
authors.affiliation: Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas and Universidad Autonoma de Madrid, 28049 Madrid, Spain.
authors.forename: Leonor
authors.initials: L
authors.lastname: Kremer
authors.affiliation: Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas and Universidad Autonoma de Madrid, 28049 Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Alonso
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032 ggg1@columbia.edu.
authors.forename: Gregg G
authors.initials: GG
authors.lastname: Gundersen
mesh_terms: D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D000080865:Formins; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D041681:NIH 3T3 Cells; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D002352:Carrier Proteins; C491464:Diap1 protein, mouse; D000080865:Formins; C515509:INF2 protein, mouse; C101203:IQ motif containing GTPase activating protein 1; D008246:Lysophospholipids; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D020703:ras GTPase-Activating Proteins; D020742:rhoA GTP-Binding Protein; C032881:lysophosphatidic acid