CD40 signal transduction

While the TNF-R family members display structural homologies in their extracellular ligand-binding domains, no obvious homologies can be detected in their intracellular domains. In particular, CD40 has no kinase domain and no known consensus sequence for binding to kinases. Yet, CD40 ligation activates protein-tyrosine kinases, including lytt and syk and induces the tyrosine phosphorylation of multiple substrates including phosphatidylinositol 3-kinase and phospholipase Cy2. The phosphorylation of the latter is consistent with the anti-CD40 induced IP, production. The inhibitory effects of protein-tyrosine kinase inhibitors and of CD45 cross-linking demonstrate the functional relevance of the CD40-induced tyrosine phosphorylation. CD40 ligation also appears to activate the serine-threonine protein kinases and, most particularly, the stress-activated protein kinases (SAPK, also known as JNK for c-jun NH2-terminal kinase). Finally, these different activation pathways result in the activation of various transcription factors including NF-kB, NF-kB-like molecules (such as p50, p6.5 (rel A), c-Rel), c-jun and NF-AT.

Through their intracytoplasmic domains, the members of the TNF-R family bind to a family of intracellular molecules, the TRAF proteins for (TNF-R)-associated factors. CRAF,/TRAF;, a 62 kDa intracellular protein, binds to the cytoplasmic domain of CD40 and to the EBV (Epstein-Barr virus)-transforming gene product LMP-1 (latent infection membrane protein 1) but not to TNF-RI, TNF-RII or Fas. CRAF,/TRAF, appears to be essential for CD40 signaling inasmuch as a mutant CD40 with a point mutation Thr-234 to Ala does not bind CRAF,/TRAF, and is functionally inactive. In addition to recruiting TRAF.,, CD40 utilized TRAF,, a 56 kDa intracellular protein that is also used by the 75 kDa TNF-R.

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