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Phosphorylation of IQGAP1 modulates its binding to Cdc42, revealing a new type of rho-GTPase regulator.

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  • 2004-09-10
Published in:
  • The Journal of biological chemistry. - 2004
Algorithms
Amino Acid Sequence
Binding Sites
Blotting, Western
Buffers
Cell Communication
Cell Line
Cell Line, Tumor
Gene Expression Regulation
Glutathione Transferase
Guanine Nucleotide Exchange Factors
Guanosine Diphosphate
Guanosine Triphosphate
Humans
Immunoprecipitation
Mass Spectrometry
Molecular Sequence Data
Mutagenesis
Nucleotides
Oligonucleotides
Phosphorylation
Plasmids
Protein Binding
Protein Conformation
Protein Kinase C
Protein Kinase C-epsilon
Protein Structure, Tertiary
Recombinant Proteins
Sequence Homology, Amino Acid
Serine
Signal Transduction
Software
Time Factors
cdc42 GTP-Binding Protein
rac1 GTP-Binding Protein
ras GTPase-Activating Proteins
rho GTP-Binding Proteins
English The Rho-GTPase Cdc42 is important for the establishment and maintenance of epithelial polarity. Signaling from Cdc42 is propagated via its effector molecules that specifically bind to Cdc42 in the GTP-bound form. The cell-cell contact regulator and actin-binding protein IQGAP1 is described as effector of Cdc42 and Rac. Unexpectedly, we show in this study that IQGAP1 bound also directly nucleotide-depleted Cdc42 (Cdc42-ND). This interaction was enhanced in the presence of phosphatase inhibitors and in epithelial cells without cell-cell contacts. Tandem mass spectrometry analysis and immunoprecipitation experiments revealed that IQGAP1 was Ser1443-phosphorylated in vivo, potentially by protein kinase Cepsilon and upon loss of cell-cell contacts. In addition, we identified two independent domains of the IQGAP1 C terminus that bound exclusively Cdc42-ND. These domains interacted with each other, favoring the binding to Cdc42-GTP. Moreover, phosphorylation on Ser1443 strongly inhibited this intramolecular interaction. Thus, we unraveled a molecular mechanism that reveals a novel type of Rho-GTPase regulator. We propose that, depending on its phosphorylation state, IQGAP1 might serve as an effector or sequester nucleotide-free Cdc42 to prevent signaling.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/47166
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