Protein complexes containing CYFIP/Sra/PIR121 coordinate Arf1 and Rac1 signalling during clathrin-AP-1-coated carrier biogenesis at the TGN

Nat Cell Biol. 2010 Apr;12(4):330-40. doi: 10.1038/ncb2034. Epub 2010 Mar 14.


Actin dynamics is a tightly regulated process involved in various cellular events including biogenesis of clathrin-coated, AP-1 (adaptor protein 1)-coated transport carriers connecting the trans-Golgi network (TGN) and the endocytic pathway. However, the mechanisms coordinating coat assembly, membrane and actin remodelling during post-TGN transport remain poorly understood. Here we show that the Arf1 (ADP-ribosylation factor 1) GTPase synchronizes the TGN association of clathrin-AP-1 coats and protein complexes comprising CYFIP (cytoplasmic fragile-X mental retardation interacting protein; Sra, PIR121), a clathrin heavy chain binding protein associated with mental retardation. The Rac1 GTPase and its exchange factor beta-PIX (PAK-interacting exchange factor) activate these complexes, allowing N-WASP-dependent and Arp2/3-dependent actin polymerization towards membranes, thus promoting tubule formation. These phenomena can be recapitulated with synthetic membranes. This protein-network-based mechanism facilitates the sequential coordination of Arf1-dependent membrane priming, through the recruitment of coats and CYFIP-containing complexes, and of Rac1-dependent actin polymerization, and provides complementary but independent levels of regulation during early stages of clathrin-AP1-coated carrier biogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factor 1 / genetics
  • ADP-Ribosylation Factor 1 / metabolism*
  • Actin-Related Protein 2-3 Complex / metabolism
  • Actins / metabolism*
  • Adaptor Protein Complex 1 / genetics
  • Adaptor Protein Complex 1 / metabolism*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Brain / metabolism
  • COS Cells
  • Cell Fractionation
  • Chlorocebus aethiops
  • Clathrin-Coated Vesicles / metabolism*
  • Endocytosis
  • Guanine Nucleotide Exchange Factors / metabolism
  • HeLa Cells
  • Humans
  • Models, Biological
  • Protein Transport
  • RNA Interference
  • Rho Guanine Nucleotide Exchange Factors
  • Swine
  • Time Factors
  • Transfection
  • Wiskott-Aldrich Syndrome Protein, Neuronal / metabolism
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism*
  • trans-Golgi Network / metabolism*


  • ARHGEF7 protein, human
  • Actin-Related Protein 2-3 Complex
  • Actins
  • Adaptor Protein Complex 1
  • Adaptor Proteins, Signal Transducing
  • CYFIP1 protein, human
  • CYFIP2 protein, human
  • Guanine Nucleotide Exchange Factors
  • RAC1 protein, human
  • Rho Guanine Nucleotide Exchange Factors
  • WASL protein, human
  • Wiskott-Aldrich Syndrome Protein, Neuronal
  • ADP-Ribosylation Factor 1
  • rac1 GTP-Binding Protein