PLCβ3 mediates cortactin interaction with WAVE2 in MCP1-induced actin polymerization and cell migration

Jagadeesh Janjanam, Giri Kumar Chandaka, Sivareddy Kotla, Rao Gadiparthi

Research output: Contribution to journalArticle

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Abstract

Monocyte chemotactic protein 1 (MCP1) stimulates vascular smooth muscle cell (VSMC) migration in vascular wall remodeling. However, the mechanisms underlying MCP1-induced VSMC migration have not been understood. Here we identify the signaling pathway associated with MCP1-induced human aortic smooth muscle cell (HASMC) migration. MCP1, a G protein-coupled receptor agonist, activates phosphorylation of cortactin on S405 and S418 residues in a time-dependent manner, and inhibition of its phosphorylation attenuates MCP1-induced HASMC G-Actin polymerization, F-Actin stress fiber formation, and migration. Cortactin phosphorylation on S405/S418 is found to be critical for its interaction with WAVE2, a member of the WASP family of cytoskeletal regulatory proteins required for cell migration. In addition, the MCP1-induced cortactin phosphorylation is dependent on PLCβ3-mediated PKCTM activation, and siRNA-mediated down-regulation of either of these molecules prevents cortactin interaction with WAVE2, affecting G-Actin polymerization, F-Actin stress fiber formation, and HASMC migration. Upstream, MCP1 activates CCR2 and Gαq/11 in a time-dependent manner, and down-regulation of their levels attenuates MCP1-induced PLCβ3 and PKCδ activation, cortactin phosphorylation, cortactin-WAVE2 interaction, G-Actin polymerization, F-Actin stress fiber formation, and HASMC migration. Together these findings demonstrate that phosphorylation of cortactin on S405 and S418 residues is required for its interaction with WAVE2 in MCP1-induced cytoskeleton remodeling, facilitating HASMC migration.

Original languageEnglish (US)
Pages (from-to)4589-4606
Number of pages18
JournalMolecular Biology of the Cell
Volume26
Issue number25
DOIs
StatePublished - Dec 15 2015

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Cortactin
Chemokine CCL2
Polymerization
Cell Movement
Actins
Smooth Muscle Myocytes
Phosphorylation
Stress Fibers
Vascular Smooth Muscle
Down-Regulation
Cytoskeletal Proteins
G-Protein-Coupled Receptors
Cytoskeleton
Small Interfering RNA

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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PLCβ3 mediates cortactin interaction with WAVE2 in MCP1-induced actin polymerization and cell migration. / Janjanam, Jagadeesh; Kumar Chandaka, Giri; Kotla, Sivareddy; Gadiparthi, Rao.

In: Molecular Biology of the Cell, Vol. 26, No. 25, 15.12.2015, p. 4589-4606.

Research output: Contribution to journalArticle

Janjanam, Jagadeesh ; Kumar Chandaka, Giri ; Kotla, Sivareddy ; Gadiparthi, Rao. / PLCβ3 mediates cortactin interaction with WAVE2 in MCP1-induced actin polymerization and cell migration. In: Molecular Biology of the Cell. 2015 ; Vol. 26, No. 25. pp. 4589-4606.
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abstract = "Monocyte chemotactic protein 1 (MCP1) stimulates vascular smooth muscle cell (VSMC) migration in vascular wall remodeling. However, the mechanisms underlying MCP1-induced VSMC migration have not been understood. Here we identify the signaling pathway associated with MCP1-induced human aortic smooth muscle cell (HASMC) migration. MCP1, a G protein-coupled receptor agonist, activates phosphorylation of cortactin on S405 and S418 residues in a time-dependent manner, and inhibition of its phosphorylation attenuates MCP1-induced HASMC G-Actin polymerization, F-Actin stress fiber formation, and migration. Cortactin phosphorylation on S405/S418 is found to be critical for its interaction with WAVE2, a member of the WASP family of cytoskeletal regulatory proteins required for cell migration. In addition, the MCP1-induced cortactin phosphorylation is dependent on PLCβ3-mediated PKCTM activation, and siRNA-mediated down-regulation of either of these molecules prevents cortactin interaction with WAVE2, affecting G-Actin polymerization, F-Actin stress fiber formation, and HASMC migration. Upstream, MCP1 activates CCR2 and Gαq/11 in a time-dependent manner, and down-regulation of their levels attenuates MCP1-induced PLCβ3 and PKCδ activation, cortactin phosphorylation, cortactin-WAVE2 interaction, G-Actin polymerization, F-Actin stress fiber formation, and HASMC migration. Together these findings demonstrate that phosphorylation of cortactin on S405 and S418 residues is required for its interaction with WAVE2 in MCP1-induced cytoskeleton remodeling, facilitating HASMC migration.",
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