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Rodríguez-Escudero, I, Oliver, MD, Andrés-Pons, A, Molina, M, Cid, VJ and Pulido, R (2011) A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes. Hum. Mol. Genet. 20:4132-42


The PTEN (phosphatase and tensin homolog) phosphatase is unique in mammals in terms of its tumor suppressor activity, exerted by dephosphorylation of the lipid second messenger PIP(3) (phosphatidylinositol 3,4,5-trisphosphate), which activates the phosphoinositide 3-kinase/Akt/mTOR (mammalian target of rapamycin) oncogenic pathway. Loss-of-function mutations in the PTEN gene are frequent in human cancer and in the germline of patients with PTEN hamartoma tumor-related syndromes (PHTSs). In addition, PTEN is mutated in patients with autism spectrum disorders (ASDs), although no functional information on these mutations is available. Here, we report a comprehensive in vivo functional analysis of human PTEN using a heterologous yeast reconstitution system. Ala-scanning mutagenesis at the catalytic loops of PTEN outlined the critical role of residues within the P-catalytic loop for PIP(3) phosphatase activity in vivo. PTEN mutations that mimic the P-catalytic loop of mammalian PTEN-like proteins (TPTE, TPIP, tensins and auxilins) affected PTEN function variably, whereas tumor- or PHTS-associated mutations targeting the PTEN P-loop produced complete loss of function. Conversely, Ala-substitutions, as well as tumor-related mutations at the WPD- and TI-catalytic loops, displayed partial activity in many cases. Interestingly, a tumor-related D92N mutation was partially active, supporting the notion that the PTEN Asp92 residue might not function as the catalytic general acid. The analysis of a panel of ASD-associated hereditary PTEN mutations revealed that most of them did not substantially abrogate PTEN activity in vivo, whereas most of PHTS-associated mutations did. Our findings reveal distinctive functional patterns among PTEN mutations found in tumors and in the germline of PHTS and ASD patients, which could be relevant for therapy.


PubMed Online version:10.1093/hmg/ddr337


Alanine/genetics; Amino Acid Sequence; Aspartic Acid/genetics; Autistic Disorder/enzymology; Autistic Disorder/genetics; Catalytic Domain; DNA Mutational Analysis; Germ-Line Mutation/genetics; Hamartoma Syndrome, Multiple/enzymology; Hamartoma Syndrome, Multiple/genetics; Humans; Molecular Sequence Data; Mutagenesis/genetics; Mutation/genetics; PTEN Phosphohydrolase/chemistry; PTEN Phosphohydrolase/genetics; Phosphatidylinositol Phosphates/metabolism; Phosphoric Monoester Hydrolases/metabolism; Saccharomyces cerevisiae/metabolism; Structure-Activity Relationship



Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status


GO:0046856: phosphatidylinositol dephosphorylation



Figure 2 showed that mutation to the PTEN (Ala substitution at the P-loop (residue 121 -131) lost the ability to dephosphorylate PIP3.

CACAO 2687



GO:0046856: phosphatidylinositol dephosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion


Seeded From UniProt


See also


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