Abstract
Continuous adhesion formation and disassembly (adhesion turnover) in the protrusions of migrating cells is regulated by unclear mechanisms. We show that p21-activated kinase (PAK)-induced phosphorylation of serine 273 in paxillin is a critical regulator of this turnover. Paxillin-S273 phosphorylation dramatically increases migration, protrusion, and adhesion turnover by increasing paxillin-GIT1 binding and promoting the localization of a GIT1-PIX-PAK signaling module near the leading edge. Mutants that interfere with the formation of this ternary module abrogate the effects of paxillin-S273 phosphorylation. PAK-dependent paxillin-S273 phosphorylation functions in a positive-feedback loop, as active PAK, active Rac, and myosin II activity are all downstream effectors of this turnover pathway. Finally, our studies led us to identify in highly motile cells a class of small adhesions that reside near the leading edge, turnover in 20-30 s, and resemble those seen with paxillin-S273 phosphorylation. These adhesions appear to be regulated by the GIT1-PIX-PAK module near the leading edge.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence / physiology
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Animals
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CHO Cells
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Cell Adhesion / physiology
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Cell Cycle Proteins / metabolism*
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Cell Membrane / metabolism*
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Cell Movement / physiology
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Cell Surface Extensions / metabolism*
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Cell Surface Extensions / ultrastructure
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Cricetinae
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Feedback, Physiological / physiology
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Fibroblasts
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Guanine Nucleotide Exchange Factors / metabolism*
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Macromolecular Substances / metabolism
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Mutation / genetics
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Myosin Type II / metabolism
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Paxillin / genetics
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Paxillin / metabolism*
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Phosphoproteins / metabolism*
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism*
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Rats
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Rho Guanine Nucleotide Exchange Factors
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Serine / metabolism
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Signal Transduction / physiology
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p21-Activated Kinases
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rac GTP-Binding Proteins / metabolism
Substances
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Cell Cycle Proteins
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Git1 protein, rat
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Guanine Nucleotide Exchange Factors
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Macromolecular Substances
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Paxillin
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Phosphoproteins
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Pxn protein, rat
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Rho Guanine Nucleotide Exchange Factors
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Serine
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Pak1 protein, rat
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Protein Serine-Threonine Kinases
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p21-Activated Kinases
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Myosin Type II
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rac GTP-Binding Proteins