Transmembrane B ephrins and their Eph receptors signal hi-directionally.
The presently claimed invention describes a cytoplasmic protein, designated PDZ-RGS3,
which binds B ephrins through a PDZ domain, and has a regulator of heterotrimeric
G protein signaling (RGS) domain. PDZ-RGS3 mediates signaling from the ephrin-B
cytoplasmic tail. SDF-1, a chemokine with a G protein coupled receptor, or BDNF,
act as chemoattractants for cerebellar granule cells, with SDF-1 action being selectively
inhibited by soluble EphB receptor. The claimed invention reveals a pathway that
links reverse signaling to cellular guidance, uncovers a novel mode of control
for G proteins, and demonstrates a mechanism for selective regulation of responsiveness
to neuronal guidance cues. Further, compositions and methods of use are provided
for modulating cell migration as a function of chemokines and GPCR interaction,
to aid in the treatment of disease states and medical conditions, including cancer
and immune responses such as allergy and autoimmune responses. In one embodiment,
a method of altering the sensitivity of a cell to a chemokine is provided using
a PDZ-RGS3 protein.
