VAM-1: a new member of the MAGUK family binds to human Veli-1 through a conserved domain

The MAGUKs (membrane associated guanylate kinase homologues) constitute a F amily of peripheral membrane proteins that function in tumor suppression an d receptor clustering by forming multiprotein complexes containing distinct sets of transmembrane, cytoskeletal, and cytoplasmic signaling proteins. H ere, we report the characterization of the human vam-1 gene that encodes a novel member of the p55 subfamily of MAGUKs. The complete cDNA sequence of VAM-1, tissue distribution of its mRNA, genomic structure. chromosomal loca lization, and Veli-1 binding properties are presented. The vam-1 gene is co mposed of 12 exons and spans approx. 115 kb. By fluorescence in situ hybrid ization the vam-1 gene was localized to 7p15-21, a chromosome region freque ntly disrupted in some human cancers. VAM-1 mRNA was abundant in human test is, brain, and kidney with lower levels detectable in other tissues. The pr imary structure of VAM-1, predicted from cDNA sequencing, consists of 540 a mino acids including a single PDZ domain near the N-terminus, a central SH3 domain, and a C-terminal GUK (guanylate kinase-like) domain. Sequence alig nment, heterologous transfection, GST pull-down experiments, and blot overl ay assays revealed a conserved domain in VAM-1 that binds to Veli-1, the hu man homologue of the LIN-7 adaptor protein in Caenorhabditis. LIN-7 is know n to play an essential role in the basolateral localization of the LET-23 t yrosine kinase receptor, by linking the receptor to LIN-2 and LIN-10 protei ns. Our results therefore suggest that VAM-I may function by promoting the assembly of a Veli-1 containing protein complex in neuronal as well as epit helial cells. (C) 2001 Elsevier Science B.V. All rights reserved.