An mDia1-INF2 formin activation cascade facilitated by IQGAP1 regulates stable microtubules in migrating cells

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 anoth...

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Bibliographic Details
Published in:Molecular biology of the cell 2016-06, Vol.27 (11), p.1797-1808
Main Authors: Bartolini, Francesca, Andres-Delgado, Laura, Qu, Xiaoyi, Nik, Sara, Ramalingam, Nagendran, Kremer, Leonor, Alonso, Miguel A, Gundersen, Gregg G
Format: Article
Language:English
Subjects:
Actins - metabolism
Amino Acid Sequence
Animals
Carrier Proteins - metabolism
Fibroblasts - metabolism
Lysophospholipids - pharmacology
Mice
Microfilament Proteins - metabolism
Microtubule-Associated Proteins - metabolism
Microtubules - metabolism
NIH 3T3 Cells
Protein Interaction Domains and Motifs
ras GTPase-Activating Proteins - metabolism
rhoA GTP-Binding Protein - metabolism
Signal Transduction
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Summary: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.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.e15-07-0489