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WISp39 binds phosphorylated Coronin 1B to regulate Arp2/3 localization and Cofilin-dependent motility.

ABSTRACT: We previously identified Waf1 Cip1 stabilizing protein 39 (WISp39) as a binding partner for heat shock protein 90 (Hsp90). We now report that WISp39 has an essential function in the control of directed cell migration, which requires WISp39 interaction with Hsp90. WISp39 knockdown (KD) resulted in the loss of directional motility of mammalian cells and profound changes in cell morphology, including the loss of a single leading edge. WISp39 binds Coronin 1B, known to regulate the Arp2/3 complex and Cofilin at the leading edge. WISp39 preferentially interacts with phosphorylated Coronin 1B, allowing it to complex with Slingshot phosphatase (SSH) to dephosphorylate and activate Cofilin. WISp39 also regulates Arp2/3 complex localization at the leading edge. WISp39 KD-induced morphological changes could be rescued by overexpression of Coronin 1B together with a constitutively active Cofilin mutant. We conclude that WISp39 associates with Hsp90, Coronin 1B, and SSH to regulate Cofilin activation and Arp2/3 complex localization at the leading edge.

SUBMITTER: Howell M

PROVIDER: S-EPMC4384738 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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WISp39 binds phosphorylated Coronin 1B to regulate Arp2/3 localization and Cofilin-dependent motility.

Howell Michael M Brickner Howard H Delorme-Walker Violaine D VD Choi Justin J Saffin Jean-Michel JM Miller Daniel D Panopoulos Andreas A DerMardirossian Céline C Fotedar Arun A Margolis Robert L RL Fotedar Rati R

The Journal of cell biology 20150323 7

We previously identified Waf1 Cip1 stabilizing protein 39 (WISp39) as a binding partner for heat shock protein 90 (Hsp90). We now report that WISp39 has an essential function in the control of directed cell migration, which requires WISp39 interaction with Hsp90. WISp39 knockdown (KD) resulted in the loss of directional motility of mammalian cells and profound changes in cell morphology, including the loss of a single leading edge. WISp39 binds Coronin 1B, known to regulate the Arp2/3 complex an ...[more]

PMID: 25800056

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Project description:Development and homeostasis of blood vessels critically depend on the regulation of endothelial cell-cell junctions. Perturbations in cell-cell junction organization and function results in developmental defects and vascular pathologies including chronic inflammation, edema and atherosclerosis. Although many aspects of blood vessel formation and homeostasis depend on cell-cell junctions, the molecular mechanisms that regulate their dynamic rearrangement are not fully understood. The VEcad-catenin complex, which constitute the molecular basis of the adherens junctions (AJ), is connected to the actin cytoskeleton and its function is regulated by cytoskeletal contraction and actin-driven plasma membrane protrusions. Junction-associated intermitted lamellipodia (JAIL) are small actin-driven protrusions at cell-cell junctions controlled by the actin related protein 2/3 (Arp2/3)-complex that contribute to the regulation of cell-cell junctions. JAIL drive VEcad dynamics within the cell-cell junction thereby being critical for monolayer integrity, cell migration and angiogenesis. The molecular mechanisms regulating JAIL during vessel development are not completely understood. Coronin 1B (Coro1B) is an actin binding protein that controls actin networks at classical lamellipodia via both Arp2/3 complex and cofilin-mediated pathways. The role of Coro1B in endothelial cell (ECs) is not fully understood. In this study we demonstrate that Coro1B is a novel component and regulator of cell-cell junctions in ECs. Immunofluorescence studies show that Coro1B colocalizes with VEcad at cell-cell junctions in monolayers of ECs. Live-cell imaging reveal that Coro1B is recruited to, and operated at, actin-driven membrane protrusions at the cell-cell junctions. Coro1B recruitment to cell-cell junctions is regulated by cytoskeleton tension. By analyzing the Coro1B interactome, we identify integrin linked kinase (ILK) as new Coro1B-associated protein. Coro1B colocalizes with α-parvin, an interactor of ILK, at the leading edge of lamellipodia protrusions. Finally, functional experiments reveal that depletion of Coro1B causes defects in actin cytoskeleton and cell-cell junctions. In matrigel vessel network assays, depletion of Coro1B results in reduced network complexity, vessel number and vessel length. Together, our findings point towards a critical role for Coro1B in the dynamic remodeling of endothelial cell-cell junction and the assembly of vessel network.

Dataset Information

WISp39 binds phosphorylated Coronin 1B to regulate Arp2/3 localization and Cofilin-dependent motility.

Publications

WISp39 binds phosphorylated Coronin 1B to regulate Arp2/3 localization and Cofilin-dependent motility.

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