Tumor Suppressors MAGI-2 Works Its Magic on PTEN

PTEN is a tumor suppressor protein that inhibits phosphatidylinositol-3' kinase (PI-3K) activity. Wu et al. used the yeast two-hybrid method to identify a protein, membrane-associated guanylate kinase inverted-2 (MAGI-2), which associates with PTEN. Protein interactions involved the second PDZ domain of MAGI-2 and the PDZ domain-binding motif located at the COOH-terminus of PTEN. Cellular localization studies indicated that some MAGI-2 and PTEN are situated at the plasma membrane near tight junctions. Much of the MAGI-2 protein localizes to the nucleus, but the significance of this is unknown. Coexpression of MAGI-2 and PTEN in 293T cells revealed that MAGI-2 enhanced the efficiency of PTEN in repressing phosphoinositide-dependent Akt activity. Adding the PTEN COOH-terminal PDZ domain-binding motif to PTEN COOH-terminal deletion mutants increased the half-life of PTEN, perhaps through sequestration by MAGI-2 at the plasma membrane. Chromosomal deletions that include the MAGI-2 locus have been observed in certain cancers. Thus, MAGI-2 may stabilize PTEN and enhance its catalytic activity, MAGI-2 might thus act as a tumor suppressor.

Wu, X., Hepner, K., Castelino-Prabhu, S., Do, D., Kaye, M.B., Yuan, X.-J., Wood, J., Ross, C., Sawyers, C.L., and Whang, Y.E. (2000) Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2. Proc. Natl. Acad. Sci. U.S.A. 97: 4233-4238. [Abstract] [Full Text]