The membrane-associated guanylate kinase (MAGUK) proteins are concentrated at the membrane-cytoskeletal interface where they facilitate the assembly of multiprotein complexes on the inner surface of the plasma membrane. Three protein-protein interaction modules characteristically define MAGUK related proteins: the PDZ domain, the SH3 domain and the guanylate kinase (GuK) domain. The closely related MAGUK proteins, MAGI-1, MAGI-2 and MAGI-3 (membrane associated guanylate kinase inverted-1 and 2), likewise contain the GuK domain and five PDZ domains; however, the SH3 domain is replaced with a WW domain. The transcripts of MAGI-1 are alternatively spliced to produce three distinct proteins having unique C-terminals. Two variants, MAGI-1a and MAGI-1b, are associated with the membrane and cytosolic fractions and are primarily expressed in the brain. The third isoform, MAGI-1c, encodes for a nuclear localization signal that localizes MAGI-1c to the nucleus, and it is primarily expressed in the liver and kidney. MAGI-2 and MAGI-3 are localized to the plasma membrane, and they contribute to protein scaffolding by associating with the protein phosphatase PTEN.