Biomedical Engineering Reference
In-Depth Information
receptor types is also apparent. Generally, low constitutive expression of TNF-R55 is observed,
with TNF-R75 expression being inducible.
Both receptor types are members of the NGF receptor superfamily and exhibit the characteristic
four (cysteine-rich) repeat units in their extracellular domain. The extracellular domains of
TNF-R55 and TNF-R75 exhibit only 28 per cent homology and their intracellular domains are
devoid of any homology, indicating the likely existence of distinct signalling mechanisms.
It appears that TNF-R55 is capable of mediating most TNF activities, whereas the biological
activities induced via the TNF-R75 receptor are more limited. For example, TNF's cytotoxic
activity, as well as its ability to induce synthesis of various cytokines and prostaglandins, is all
mediated mainly/exclusively by TNF-R55. TNF-R75 appears to play a more prominent role in
the induction of synthesis of T-lymphocytes. All of the biological activities mediated by TNF-
R75 can also be triggered via TNF-R55, and usually at much lower densities of receptors. TNF-
R75 thus appears to play more of an accessory role, mainly to enhance effects mediated via
TNF-R55.
Binding of TNF to either receptor type results in oligomerization of the receptor (Figure 9.5).
Indeed, antibodies raised against the extracellular domains of the receptors can induce TNF
activity, indicating that the major/sole function of the TNF ligand is to promote such cluster-
ing of receptors. In most cases, binding of TNF to TNF-R55 results in rapid internalization
of the ligand—receptor complex followed by lysosomal degradation. In contrast, binding of
TNF to TNF-R75 does not induce such receptor internalization. In some cases, ligand binding
appears to activate selective cleavage of the extracellular domain, resulting in the release of
soluble TNF-R75. Soluble forms of both receptor types have been found in both the blood and
urine.
The exact molecular mechanisms by which TNF-induced signal transduction are mediated
remain to be characterized in detail. Oligomerization of the receptors is often followed by their
phosphorylation, most likely by accessory kinases that associate with the intracellular domain
of the receptor (neither receptor type displays intrinsic protein kinase activity). The existence
of several phosphoproteins capable of associating with (the intracellular domain of) TNF-R55
and TNF-R75 have also been established. Following clustering of the TNF receptors, these
TNF (Trimer)
TNF
-R55
Cell membrane
Cytosol
Intracellular
signalling
Figure 9.5
TNF binding to its receptor (TNF-R55), with resulting clustering of the receptor and generation
of intracellular signals. Binding of TNF to its other receptor (TNF-R75) also induces receptor clustering. (See
text for details)
Search WWH ::
Custom Search