Defects in actin-cap formation in Vav-deficient mice implicate an actin requirement for lymphocyte signal transduction

Curr Biol. 1998 May 7;8(10):563-72. doi: 10.1016/s0960-9822(98)70225-8.


Background: Antigen-receptor interactions on lymphocytes result in local clustering of actin, receptors and signaling molecules into an asymmetric membrane structure termed a cap. Although actin polymerization is known to be required, the mechanisms underlying cap formation are unclear. We have studied the events underlying cap formation using mice bearing a null mutation in vav (vav-/-), a gene that encodes a guanine-nucleotide exchange factor for the GTPase Rac.

Results: Lymphocytes from vav-/- mice failed to form T-cell receptor caps following activation and had a defective actin cytoskeleton. The vav-/- T cells were deficient in interleukin-2 (IL-2) production and proliferation, and the peak of Ca2+ mobilization was reduced although of normal duration. Activation of Jun N-terminal kinase or stress-activated kinase (JNK or SAPK) and mitogen-activated protein kinase (MAPK) and the induction of the transcription factor NF-ATc1 and egr-1 genes was normal. Despite the reduced Ca2+ mobilization, translocation of cytoplasmic NF-ATc to the nucleus was normal, reflecting that the lower levels of Ca2+ in vav-/- cells were still sufficient to activate calcineurin. Treatment of lymphocytes with cytochalasin D, which blocks actin polymerization, inhibited cap formation and produced defects in signaling and IL-2 transcriptional induction in response to antigen-receptor signaling that were nearly identical to those seen in vav-/- cells. In transfection studies, either constitutively active Vav or Rac could complement constitutively active calcineurin to activate NF-AT-dependent transcription.

Conclusions: These results indicate that Vav is required for cap formation in lymphocytes. Furthermore, the correlation between cap formation, IL-2 production and proliferation supports the hypothesis that an actin-dependent pathway is a source of specialized growth regulatory signals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism*
  • Animals
  • Cell Cycle Proteins*
  • Cytoskeleton
  • DNA-Binding Proteins / metabolism
  • Humans
  • Jurkat Cells
  • Mice
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-vav
  • Receptor-CD3 Complex, Antigen, T-Cell / metabolism
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction*
  • T-Lymphocytes / metabolism*
  • Transcription Factors / metabolism
  • Transcription, Genetic


  • Actins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • NFATC Transcription Factors
  • NFATC1 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-vav
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Receptors, Antigen, T-Cell
  • Transcription Factors
  • VAV1 protein, human
  • Vav1 protein, mouse