Bag-1 also has anti-apoptotic effects that are independent of Bcl-2; it binds to multiple receptor tyrosine kinases and enhances their ability to inhibit apoptosis [ 44], and it interacts with the heat shock proteins HSC70 and HSP70 [ 45].
The need for "balanced" signaling provides an explanation for how a signaling system in which a single ligand binds to multiple receptor subtypes may develop naturally, although some of these active downstream pathways have diametrically opposite cellular effects [ 17].
Myriad interactions in nature use polyvalent binding, where multiple ligands on one entity bind to multiple receptors on another: antibody antigen interactions, virus−cell binding, cell cell signaling, and others.
Neurotrophin proteins bind to multiple receptors (p75, TrkA-C) to modulate survival, functional and degenerative intracellular signaling and synaptic function.
Privileged structures bind to multiple receptors with high affinity, thus aiding the development of novel biologically active compounds.
Likewise, many recent studies revealed that lactoferrin could bind to multiple receptors on hepatocytes.
The major-cluster chemokines usually bind to multiple receptors and often do not correspond well between species.
CCN2 can bind to multiple receptors and activate divergent signaling pathways, including TGF- β, p38 MAPK [ 23], PI3K [ 24], and Rho GTPase [ 25].
In addition, ligands can bind to multiple receptor and/or co-receptor combinations to stimulate different downstream target gene expression.
Echistatin, a polypeptide found in snake venom, binds to multiple integrin receptors with high affinity [8], [27] and was used as a positive control.
