Germ-line mutations in PTEN are linked to three rare autosomal dominant syndromes: Cowden Disease, Bannayan- Zonana syndrome and Lhermitte-Duclose disease

The tumor suppressor gene PTEN is one of the most frequently mutated genes involved in the development of human cancer (Cantley and Neel, 1999; Li et al., 1997a; Steck et al., 1997). PTEN mutations are found in a wide variety of tumors such as glioblastomas, endometrial carcinomas, advanced prostate cancers and melanoma cells (Cairns et al., 1997; Guldberg et al., 1997; Li et al., 1997a; Liu et al., 1997; Rasheed et al., 1997; Risinger et al., 1997; Tashiro et al., 1997; Wang et al., 1997). Germ-line mutations in PTEN are linked to three rare autosomal dominant syndromes: Cowden Disease, BannayanZonana syndrome and Lhermitte-Duclose disease (Liaw et al., 1997; Marsh et al., 1997). A common feature of these syndromes is a predisposition for the development of hamartomas, benign tumors that have differentiated but disorganized cells. The PTEN protein contains the phosphatase signature motif HCXXGXXRS/T that is found in all protein tyrosine phosphatases (Denu et al., 1996; Li and Sun, 1997; Li et al., 1997a; Steck et al., 1997). This phosphatase domain is the most common site of germline or sporadic PTEN mutations (Myers and Tonks, 1997). In vitro studies have demonstrated that PTEN can dephosphorylate phosphotyrosine, phosphoserine and phosphothreonine residues on artificial substrates (Li and Sun, 1997; Myers et al., 1997). Recently, PTEN has been shown to have strong in vitro and in vivo activity for the 3′ position of phosphatidyl inositol 3,4,5 trisphosphate (PIP3) (Maehama and Dixon, 1998). PIP3 is produced by the catalytic activity of phosphatidyl inositol 3 kinase (PI3K) and can act as a membrane-embedded second messenger for the activation of a variety of signaling molecules. A number of Pten mutant mice have been described (Di Cristofano et al., 1998; Podsypanina et al., 1999; Suzuki et al., 1998). Although the spectrum of disorders affecting the Pten mutant mice varies between the different strains, all homozygous Pten mutants exhibit early embryonic lethality (E7.5-E9.5) and the heterozygotes display a predisposition to tumor development (Di Cristofano et al., 1998; Podsypanina et al., 1999; Suzuki et al., 1998). Consistent with the role for PTEN as a PIP3 phosphatase, Pten mutant cells exhibit increased PIP3 signaling (Stambolic et al., 1998; Sun et al., 1999). The C. elegans gene daf-18 encodes a distant PTEN homolog (Gil et al., 1999; Mihaylova et al., 1999; Ogg and Ruvkun, 1998; Rouault et al., 1999). In addition to a conserved phosphatase domain, daf-18 encodes a large non-homologous C-terminal region (Ogg and Ruvkun, 1998). Daf-18 mutants can suppress the mutant phenotypes of daf-2, the C. elegans insulin-like receptor, and age-1, the C. elegans PI3K (Gil et al., 1999; Mihaylova et al., 1999; Ogg and Ruvkun, 1998; Rouault et al., 1999). 5365 Development 126, 5365-5372 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 DEV8662