TrkA receptors for nerve growth factor (NGF) are thought to signal not only at the plasma membrane, but also during transport in vesicles from axons to the cell body where nuclear targets are located. Lou et al . describe association of the TrkA receptor tyrosine kinase with proteins that may help coordinate such targeting of receptors for retrograde transport and also mediate cross-talk of the TrkA receptor signals with G protein signaling pathways. (Ready for some acronyms? Hang on tight--its not as bad as it looks at first!) In a two-hybrid screen for proteins that interact with the juxtamembrane domain of Trk, the authors detected the protein GIPC. GIPC (GAIP-interacting protein, COOH terminus) is a protein that interacts through a PDZ protein interaction domain with GAIP (Gα-interacting protein). GAIP is a regulator of G protein signaling (or RGS protein) that increases GTPase activity, and thus inactivates, the Gα i subunit of G proteins. GAIP is found on clathrin-coated vesicles and appears to function in control of membrane trafficking. GAIP, GIPC, and TrkA were detected together in complexes in transfected cells, and endogenous GIPC was associated with phosphorylated (activated) Trk A in retrograde transport vesicles. Overexpression of GIPC selectively inhibited signaling from TrkA to activate the mitogen-activated protein kinases ERK1 and ERK2, but did not suppress other Trk A signals. The authors propose that GIPC, like other PDZ domain-containing proteins, contributes to organization of signaling proteins and may link receptor tyrosine kinase and G protein signaling pathways. X. Lou, H. Yano, F. Lee, M. V. Chao, M. G. Farquhar, GIPC and GAIP form a complex with TrkA: A putative link between G protein and receptor tyrosine kinase pathways. Mol. Biol. Cell 12 , 615-627 (2001). [Abstract] [Full Text]