Abstract
Cell polarization is essential for many biological processes, including directed cell migration, and loss of polarity contributes to pathological conditions such as cancer. The Par complex (Par3, Par6, and PKCζ) controls cell polarity in part by recruiting the Rac-specific guanine nucleotide exchange factor T-lymphoma invasion and metastasis 1 (Tiam1) to specialized cellular sites, where Tiam1 promotes local Rac1 activation and cytoskeletal remodeling. However, the mechanisms that restrict Par-Tiam1 complex activity to the leading edge to maintain cell polarity during migration remain unclear. We identify the Rac-specific GTPase-activating protein (GAP) breakpoint cluster region protein (Bcr) as a novel regulator of the Par-Tiam1 complex. We show that Bcr interacts with members of the Par complex and inhibits both Rac1 and PKCζ signaling. Loss of Bcr results in faster, more random migration and striking polarity defects in astrocytes. These polarity defects are rescued by reducing PKCζ activity or by expressing full-length Bcr, but not an N-terminal deletion mutant or the homologous Rac-GAP, Abr, both of which fail to associate with the Par complex. These results demonstrate that Bcr is an integral member of the Par-Tiam1 complex that controls polarized cell migration by locally restricting both Rac1 and PKCζ function.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Astrocytes / cytology*
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Astrocytes / metabolism
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Cell Adhesion Molecules
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Cell Cycle Proteins
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Cell Movement / genetics*
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Cell Polarity / genetics*
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Cell Polarity / physiology
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Cells, Cultured
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GTPase-Activating Proteins / metabolism
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Guanine Nucleotide Exchange Factors / metabolism
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Mice
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Mice, Knockout
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Neuropeptides / antagonists & inhibitors
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Neuropeptides / biosynthesis
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Neuropeptides / metabolism
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism
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Proto-Oncogene Proteins c-bcr / genetics*
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Proto-Oncogene Proteins c-bcr / metabolism
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Signal Transduction
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T-Lymphoma Invasion and Metastasis-inducing Protein 1
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rac1 GTP-Binding Protein / antagonists & inhibitors
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rac1 GTP-Binding Protein / biosynthesis
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rac1 GTP-Binding Protein / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Cell Adhesion Molecules
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Cell Cycle Proteins
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GTPase-Activating Proteins
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Guanine Nucleotide Exchange Factors
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Neuropeptides
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Par6 protein, mouse
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Pard3 protein, mouse
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Rac1 protein, mouse
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T-Lymphoma Invasion and Metastasis-inducing Protein 1
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Tiam1 protein, mouse
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Bcr protein, mouse
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Proto-Oncogene Proteins c-bcr
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protein kinase C zeta
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Protein Kinase C
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rac1 GTP-Binding Protein