vendredi 4 mai 2012

Mutated genes in cancer (68) – PTEN


In databases:

● Entrez ( 5728 or PTEN
● Ensembl ( ENSG00000185920
● UniProt ( P60484
● GeneCards ( PTEN
● HGNC ( 9588 or PTEN
Enzyme Number (IUBMB): EC, EC, EC

Gene locus :


Protein name:

Phosphatase and tensin homolog

Protein Size:

403 amino acids; about 47 kDa


PTEN acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and  threonine-phosphorylated proteins. It also acts as a lipid phosphatase, an activity that is critical for its tumor suppressor function. By negatively regulating intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells, PTEN antagonizes the PI3K-AKT/PKB signaling pathway, thereby modulating cell cycle progression and cell survival.

Cancer-related alterations:

Germinal PTEN mutations have been documented in Cowden disease and in Bannayan-Riley-Ruvalcaba phenotype; they are observed along the various exons of the gene except the 9th (never described) and the 1st (very few reports); a mutational hot spot is observed in exon 5 (amino acids 130-131 and 173) in relation with the catalytic core motif; in the great majority of the cases, inactivating mutations are observed, either by protein truncation, or by “missense” mutation within the phosphatase domain.

Somatic PTEN mutations are observed in several tumor types, notably those affecting vulva, endometrium, salivary glands, CNS (glioma), prostate, skin (malignant melanoma); they lead to a biallelic inactivation of the gene either by homozygous deletion, or by a combination of point mutation (mainly substitution) and a large deletion of the second allele. As with germinal mutations, mutational hot spots correspond to aminoacids 130-131 and 173.

Defects in PTEN are a cause of Cowden disease (CD), which is an autosomal dominant cancer predisposition syndrome associated with elevated risk for tumors of the breast, thyroid and skin. The predominant phenotype for CD is multiple hamartoma syndrome, in many organ systems including the breast (70% of CD patients), thyroid (40-60%), skin, CNS (40%), gastrointestinal tract. Affected individuals are at an increased risk of both breast and thyroid cancers. Trichilemmomas (benign tumors of the hair follicle infundibulum), and mucocutaneous papillomatosis (99%) are hallmarks of CD.
Defects in PTEN are the cause of Lhermitte-Duclos disease (LDD), which is characterized by dysplastic gangliocytoma of the cerebellum which often results in cerebellar signs and seizures. LDD and CD seem to be the same entity, and are considered as hamartoma-neoplasia syndromes.

Defects in PTEN are a cause of Bannayan-Zonana syndrome (BZS), also known as Bannayan-Riley-Ruvalcaba syndrome (BRRS). In BZS there seems not to be an increased risk of malignancy. It has a partial clinical overlap with CD. BZS is characterized by the classic triad of macrocephaly, lipomatosis and pigmented macules of the gland penis.

Defects in PTEN are a cause of Proteus syndrome. Proteus syndrome is a hamartomatous disorder characterized by overgrowth of multiple tissues, connective tissue and epidermal naevi, and vascular malformations. Tumors, mostly benign but some malignant, have also been reported in Proteus syndrome, generally presenting by the age of 20 years and including papillary adenocarcinoma of the testis, meningioma, and cystadenoma of the ovaries.

A microdeletion of chromosome 10q23 involving PTEN and BMPR1A is a cause of chromosome 10q23 deletion syndrome. This syndrome shows overlapping features of the following three disorders: Bannayan-Zonana syndrome, Cowden disease and juvenile polyposis syndrome.

References (open access):

Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Steelman LS, Chappell WH, Abrams SL, Kempf RC, Long J, Laidler P, Mijatovic S, Maksimovic-Ivanic D, Stivala F, Mazzarino MC, Donia M, Fagone P, Malaponte G, Nicoletti F, Libra M, Milella M, Tafuri A, Bonati A, Bäsecke J, Cocco L, Evangelisti C, Martelli AM, Montalto G, Cervello M, McCubrey JA. Aging (Albany NY). 2011 Mar;3(3):192-222.

PTEN Tumor Suppressor Network in PI3K-Akt Pathway Control. Georgescu MM. Genes Cancer. 2010 Dec;1(12):1170-7.

Characterisation of the PTEN inhibitor VO-OHpic. Mak LH, Vilar R, Woscholski R. J Chem Biol. 2010 Oct;3(4):157-63.

The PTEN phosphatase controls intestinal epithelial cell polarity and barrier function: role in colorectal cancer progression. Langlois MJ, Bergeron S, Bernatchez G, Boudreau F, Saucier C, Perreault N, Carrier JC, Rivard N. PLoS One. 2010 Dec 23;5(12):e15742.

1 commentaire: