Bidirectional Signaling in Other Receptor Ligand Systems

Bidirectional signal transduction is not a rare phenomenon. It has been documented for several other members of the TNF and TNFR families, Eph receptors and ephrins, integrins and cell adhesion molecules, and B7 and its receptors.

Among the members of the TNF family reverse signaling has been demonstrated for membrane-integrated TNF, CD27 ligand, CD30 ligand, CD40 ligand, CD95 ligand, CD137 ligand, OX40 ligand, LIGHT, TRAIL, and TRANCE. These receptor/ligand systems can therefore signal bidirectionally and so exert their manifold and diverse activities on activation, proliferation, differentiation, and survival or death of immune cells and non-immune cells (Eissner et al., 2004).

The Eph receptors are a large family of receptor protein tyrosine kinases and are highly conserved during evolution. They participate in the regulation of embryo patterning, neural development, axon guidance, angiogenesis, and vascular network assembly. Their ligands are the ephrins and some ephrins are transmembrane proteins. Together with their Eph receptors these ephrins can signal bidi-rectionally and activate respective downstream signaling cascades simultaneously, leading to the above mentioned biological activities (Cowan and Henckemeyer, 2002; Wilkinson, 2000).

Integrins transduce signals into the cells they are expressed on upon binding to a ligand. Among the integrin ligands are cell adhesion molecules, such as ICAM-1, which themselves are expressed as cell surface molecules and can transmit signals into the cells they are expressed on (Chirathaworn et al., 1995; Holland and Owens, 1997).

In addition, another kind of two-way signaling has been described for integrins, referred to as inside-out and outside-in signaling (Qin et al., 2004). Ligands for integrins can also be components of the extracellular matrix and binding transmits a signal into the integrin-expressing cell (outside-in signaling). Cell activation can change the conformation of the extracellular domain of the integrin and thereby the affinity to its ligand (inside-out signaling). This type of two-way signaling of integrins is not identical to the bidirectional signaling discussed here since it often affects only one cell, the one which expresses the integrin.

The CD137 receptor/ligand system shares some features with the B7/CD28 costimulatory system. Both, B7 and CD137 ligand are expressed constitutively on dendritic cells but expression is enhanced upon activation. Both engage a receptor on T cells which provides costimulation. Interestingly, it has recently been demonstrated that the two receptor/ligand systems also share bidirectional signaling, since

B7 also is able to transduce a signal into dendritic cells. The functional activities of B7 signaling are however more complex since two ligands (B7.1 and B7.2) and two receptors (CD28 and CTLA-4) exist. The reverse signal through B7 can either tolerize dendritic cells or activate then, depending on whether B7 proteins are engaged by CTLA-4 or by CD28, respectively (Greenwald et al., 2005; Orabona et al., 2004).

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