A PDZ protein regulates the distribution of the transmembrane semaphorin, M-SemF

M-SemF is a membrane-associated, neurally enriched member of the semaphorin family of axon guidance signals. We considered whether the cytoplasmic dom ain of M-SemF might possess a signaling function and/or might control the d istribution of M-SemF on the cell surface. We identify a PDZ-containing neu ral protein as an M-SemF cytoplasmic domain-associated protein (SEMCAP-1), SEMCAP-2 is a closely related nonneuronal protein. SEMCAP-1 has recently al so been identified as GIPC, by virtue of its interaction with the RGS prote in GAIP in vitro (De Vries, L., Lou, X., Zhao, G., Zheng, B., and Farquhar, M.G. (1998) Proc. Natl, Acad, Sci, U. S. A, 95, 12340-12345), Expression s tudies support the notion that SEMCAP-1(GIPC) interacts with M-SemF, but no t GAIP, in brain. Lung SEMCAP-2 and SEMCAP-1(GIPC) are potential partners f or both GAIP and M-SemF. The protein interaction requires the single PDZ do main of SEMCAP-1(GIPC) and the carboxyl-terminal four residues of M-SemF, E SSV, While SEMCAP-1(GIPC) also interacts with SemC, it does not interact wi th other proteins containing a class I PDZ binding motif, nor does M-SemF i nteract with other class I PDZ proteins. Coexpression of SEMCAP-1(G;IPC) in duces the redistribution of dispersed M-SemF into detergent-resistant aggre gates in HEK293 cells. Thus, SEMCAP-1(GIPC) appears to regulate the subcell ular distribution of M-SemF in brain, and SEMCAPs could link M-SemF to G pr otein signal transduction pathways.