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A Cortactin-CD2-associated protein (CD2AP) complex provides a novel link between epidermal growth factor receptor endocytosis and the actin cytoskeleton.

Growth factor regulation of the cortical actin cytoskeleton is fundamental to a wide variety of cellular processes. The cortical actin-associated protein, cortactin, regulates the formation of dynamic actin networks via the actin-related protein (Arp)2/3 complex and hence is a key mediator of such responses. In order to reveal novel roles for this versatile protein, we used a proteomics-based approach to isolate cortactin-interacting proteins. This identified several proteins, including CD2-associated protein (CD2AP), as targets for the cortactin Src homology 3 domain. Co-immunoprecipitation of CD2AP with cortactin occurred at endogenous expression levels, was transiently induced by epidermal growth factor (EGF) treatment, and required the cortactin Src homology 3 domain. The CD2AP-binding site for cortactin mapped to the second of three proline-rich regions. Because CD2AP is closely related to Cbl-interacting protein of 85 kDa (CIN85), which regulates growth factor receptor down-regulation via complex formation with Cbl and endophilin, we investigated whether the CD2AP-cortactin complex performs a similar function. EGF treatment of cells led to transient association of Cbl and the epidermal growth factor receptor (EGFR) with a constitutive CD2AP-endophilin complex. Cortactin was recruited into this complex with slightly delayed kinetics compared with Cbl and the EGFR. Immunofluorescence analysis revealed that the EGFR, CD2AP, and cortactin co-localized in regions of EGF-induced membrane ruffles. Therefore, by binding both CD2AP and the Arp2/3 complex, cortactin links receptor endocytosis to actin polymerization, which may facilitate the trafficking of internalized growth factor receptors.

Pubmed ID: 12672817

Authors

  • Lynch DK
  • Winata SC
  • Lyons RJ
  • Hughes WE
  • Lehrbach GM
  • Wasinger V
  • Corthals G
  • Cordwell S
  • Daly RJ

Journal

The Journal of biological chemistry

Publication Data

June 13, 2003

Associated Grants

None

Mesh Terms

  • Actin-Related Protein 2
  • Actin-Related Protein 3
  • Actins
  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Binding Sites
  • Blotting, Western
  • Carrier Proteins
  • Cell Line
  • Cortactin
  • Cytoskeletal Proteins
  • Cytoskeleton
  • Down-Regulation
  • Electrophoresis, Polyacrylamide Gel
  • Endocytosis
  • Epidermal Growth Factor
  • Fluorescent Antibody Technique, Indirect
  • Glutathione Transferase
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Kinetics
  • Mass Spectrometry
  • Microfilament Proteins
  • Microscopy, Fluorescence
  • Models, Biological
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation
  • Plasmids
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteins
  • Receptor, Epidermal Growth Factor
  • Recombinant Fusion Proteins
  • Sequence Homology, Amino Acid
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Transfection
  • Tumor Cells, Cultured
  • src Homology Domains