CD38 is associated with lipid rafts and upon receptor stimulation leads to Akt/protein kinase B and Erk activation in the absence of the CD3-zeta immune receptor tyrosine-based activation motifs

J Biol Chem. 2002 Jan 4;277(1):13-22. doi: 10.1074/jbc.M107474200. Epub 2001 Oct 31.

Abstract

T lymphocytes can be activated via the T cell receptor (TCR) or by triggering through a number of other cell surface structures, including the CD38 co-receptor molecule. Here, we show that in TCR+ T cells that express a CD3-zeta lacking the cytoplasmic domain, cross-linking with CD38- or CD3-specific monoclonal antibodies induces tyrosine phosphorylation of CD3-epsilon, zeta-associated protein-70, linker for activation of T cells, and Shc. Moreover, in these cells, anti-CD38 or anti-CD3 stimulation leads to protein kinase B/Akt and Erk activation, suggesting that the CD3-zeta-immunoreceptor tyrosine-based activation motifs are not required for CD38 signaling in T cells. Interestingly, in unstimulated T cells, lipid rafts are highly enriched in CD38, including the T cells lacking the cytoplasmic tail of CD3-zeta. Moreover, CD38 clustering by extensive cross-linking with an anti-CD38 monoclonal antibody and a secondary antibody leads to an increased resistance of CD38 to detergent solubilization, suggesting that CD38 is constitutively associated with membrane rafts. Consistent with this, cholesterol depletion with methyl-beta-cyclodextrin substantially reduces CD38-mediated Akt activation while enhancing CD38-mediated Erk activation. CD38/raft association may improve the signaling capabilities of CD38 via formation of protein/lipid domains to which signaling-competent molecules, such as immunoreceptor tyrosine-based activation motif-bearing CD3 molecules and protein-tyrosine kinases, are recruited.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase
  • ADP-ribosyl Cyclase 1
  • Adaptor Proteins, Signal Transducing*
  • Adaptor Proteins, Vesicular Transport*
  • Animals
  • Antigens, CD*
  • Antigens, Differentiation / physiology*
  • CD3 Complex / physiology
  • Carrier Proteins / physiology
  • Cell Line
  • Cholesterol / physiology
  • Enzyme Activation
  • Membrane Glycoproteins
  • Membrane Microdomains / metabolism*
  • Membrane Proteins / physiology*
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • NAD+ Nucleosidase / physiology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / physiology
  • Phosphorylation
  • Protein Serine-Threonine Kinases*
  • Protein-Tyrosine Kinases / physiology
  • Proteins / metabolism
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Receptors, Antigen, T-Cell / physiology*
  • Shc Signaling Adaptor Proteins
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Tyrosine / metabolism
  • ZAP-70 Protein-Tyrosine Kinase

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Antigens, CD
  • Antigens, Differentiation
  • CD3 Complex
  • Carrier Proteins
  • Lat protein, mouse
  • Membrane Glycoproteins
  • Membrane Proteins
  • Phosphoproteins
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, Antigen, T-Cell
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • antigen T cell receptor, zeta chain
  • Tyrosine
  • Cholesterol
  • Protein-Tyrosine Kinases
  • ZAP-70 Protein-Tyrosine Kinase
  • Zap70 protein, mouse
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • ADP-ribosyl Cyclase
  • Cd38 protein, mouse
  • NAD+ Nucleosidase
  • ADP-ribosyl Cyclase 1

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