Together with the data from genetic analyses, our findings lead us to propose that mKsr-1 may control MAP kinase signaling by serving as a scaffold protein that links MEK and its substrate ERK.

We have examined the influence of the V1IV2 region of the human immunodeficiency virus type 1 (HIV-1) gpl20 on certain biologic properties of the virus. We observed that on the genomic background of the T-cell-line-tropic strain, HIV-1sF2mc, both the Vi and V2 domains of the macrophage-tropic strain, HIV-1SF162mc, in addition to the required V3 domain, are necessary to attain full macrophage tropism. Furthermore, the V2 domain modulates the sensitivity of HIV-1 to soluble CD4 neutralization. Structural studies of recombinant and mutant envelope glycoproteins suggest that the function of the V1/V2 region is to interact with the V3 domain and confer on the envelope gpl20 of HIV-lSF2mc a conformation more similar to that of the macrophage-tropic strain HIV-lSF162mc* The conformation of the envelope gpl20 appears to be strain specific and plays an important role in determining HIV-1 tissue tropism and sensitivity to soluble CD4 neutralization.

The rat substance P (SP) receptor cDNA has been transfected into cultured rat KNRK cells, and a stable cell line expressing functional SP receptors established. Upon stimulation with SP, these cells responded by simultaneously activating two signaling pathways: the mobilization of intracellular Ca2+ and the raising of cyclic adenosine triphosphate (cAMP) levels. Both Ca2+ and cAMP responses were elicited in a similar dose-dependent manner with half maximal concentrations of approximately 5 x 10(-10) M. Following ionomycin treatment SP-dependent Ca2+ responses were abolished, whereas cAMP responses were preserved. Forskolin eliminated the SP-dependent cAMP elevation, however, the SP-induced Ca2+ mobilization remained unchanged. Furthermore, treatment with phorbol esters had no significant effect on either of the two SP-induced responses. Thus it appears that the SP receptor is capable of independently activating Ca2+ mobilization and cAMP pathways. These results may provide new insights for further understanding the diverse activities of SP in various systems in vitro and in vivo.

Measles virus (MV) encodes the fusion protein (F) that mediates cell fusion and intercellular spread of the virus, and is homologous to the carboxy terminus of the neuropeptide substance P (SP). In addition, the oligopeptide Z-D-Phe-L-PheGly, also homologous to F and SP, inhibits MV fusion with target cells. These observations raise the question of whether MV uses the SP receptor (SPR) during a specific phase of its infectious cycle. In this report, we examine the structural and functional consequences of this interaction and show, using cross-linking studies, that MV and SP specifically bind to a 52-58-kD protein, previously reported to comprise the SPR on human IM-9 lymphoblasts. Moreover, bound MV and SP are shown to reciprocally displace each other from these cells. In addition, we demonstrate that anti-SP antisera inhibits the cell-to-cell spread of MV, and that SP blocks MV fusion with target cells. These results indicate the presence of MV-SPR interactions during viral fusion, and suggest possible novel mechanisms for viral entry into cells. (J. Clin. Invest. 1990.