Unique biochemical properties of the protein tyrosine phosphatase activity of PTEN—Demonstration of different active site structural requirements for phosphopeptide and phospholipid phosphatase activities of PTEN

Chia, Joel; Gajewski, Joanna E.; Xiao, Yi; Zhu, Hong; Cheng, Heung‐Chin

doi:10.1016/j.bbapap.2010.05.009

Cited by 21 publications

(39 citation statements)

References 32 publications

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“…76 Subsequently, R130 binds to the D3-phopsphate of PIP 3 and transfers it to neighboring C124; this interaction is possibly lost due to mutations at position 130. 76 Previous studies indicate that mutations within the active site pocket, in addition to p.R173C/H mutants, exhibit inactivated phosphatase activity, 70,77-79 revealing a possible long-range communication, further implicating this region as a possible mutation-driven allosteric interface. R173 forms a saltbridge with D324 stabilizing the rich hydrogen bond network within the interface.…”

Section: Discussionmentioning

confidence: 97%

“…) as well as interaction with neighboring essential catalytic residues C124 and D92 would disrupt overall function of PTEN. The normal catalytic mechanism involves D92 donating a proton to the bridging oxygen of its substrate PIP 3 . Subsequently, R130 binds to the D3‐phopsphate of PIP 3 and transfers it to neighboring C124; this interaction is possibly lost due to mutations at position 130 .…”

Section: Discussionmentioning

confidence: 99%

“…The normal catalytic mechanism involves D92 donating a proton to the bridging oxygen of its substrate PIP 3 . Subsequently, R130 binds to the D3‐phopsphate of PIP 3 and transfers it to neighboring C124; this interaction is possibly lost due to mutations at position 130 . Previous studies indicate that mutations within the active site pocket, in addition to p.R173C/H mutants, exhibit inactivated phosphatase activity, revealing a possible long‐range communication, further implicating this region as a possible mutation‐driven allosteric interface.…”

Section: Discussionmentioning

confidence: 99%

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Structural mutation analysis of PTEN and its genotype‐phenotype correlations in endometriosis and cancer

Smith

Briggs

2016

Proteins

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The phosphatase and tensin homolog deleted on chromosome ten (PTEN) gene encodes a tumor suppressor phosphatase that has recently been found to be frequently mutated in patients with endometriosis, endometrial cancer and ovarian cancer. Here, we present the first computational analysis of 13 somatic missense PTEN mutations associated with these phenotypes. We found that a majority of the mutations are associated in conserved positions within the active site and are clustered within the signature motif, which contain residues that play a crucial role in loop conformation and are essential for catalysis. In silico analyses were utilized to identify the putative effects of these mutations. In addition, coarse-grained models of both wild-type (WT) PTEN and mutants were constructed using elastic network models to explore the interplay of the structural and global dynamic effects that the mutations have on the relationship between genotype and phenotype. The effects of the mutations reveal that the local structure and interactions affect polarity, protein structure stability, electrostatic surface potential, and global dynamics of the protein. Our results offer new insight into the role in which PTEN missense mutations contribute to the molecular mechanism and genotypic-phenotypic correlation of endometriosis, endometrial cancer and ovarian cancer.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Structural mutation analysis of PTEN and its genotype‐phenotype correlations in endometriosis and cancer

Smith

Briggs

2016

Proteins

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“…D92 matches the position of aspartic acid in the WPD loop of PTP1B, which acts as a general acid in the catalytic mechanism 37 . D92 is a critical residue in the PTEN catalytic pocket, but its role in the reaction mechanism remains uncertain 25,37,61 . Our data support previous findings that all mutations except D92N are damaging 25 .…”

Section: Discussionmentioning

confidence: 99%

A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotypes relationships

Mighell

Evans-Dutson

O’Roak

2018

Preprint

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Phosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD). To empower new insights into PTEN function and clinically relevant genotype-phenotype relationships, we systematically evaluated the effect of PTEN mutations on lipid phosphatase activity in vivo. Using a massively parallel approach that leverages an artificial humanized yeast model, we derived high-confidence estimates of functional impact for 7,244 single amino acid PTEN variants (86% of possible). These data uncovered novel insights into PTEN protein structure, biochemistry, and mutation tolerance. Variant functional scores can reliably discriminate likely pathogenic from benign alleles. Further, 32% of ClinVar unclassified missense variants are phosphatase deficient in our assay, supporting their reclassification. ASD associated mutations generally had less severe fitness scores relative to PHTS associated mutations (p = 7.16x10 -5 ) and a higher fraction of hypomorphic mutations, arguing for continued genotype-phenotype studies in larger clinical datasets that can further leverage these rich functional data. MAIN TEXTRecent large-scale exome sequencing studies have highlighted the abundance of protein-coding variation in the human population 1 . It remains challenging to predict variant pathogenicity and clinical outcomes, especially for genes with pleiotropic effects. With most rare variants private to a single family or individual, using traditional approaches to establish pathogenicity such as variant segregation within a pedigree or identification in independent patients is infeasible. Even for well-studied genes, hundreds of variants are currently defined as variants of uncertain significance (VUS). Moreover, purely computational approaches still suffer from high false positive rates 2 and subjective interpretations that limit the clinical utility of these predictions. To address these challenges for genes of clinical importance, one proposed approach is to prospectively measure the functional effects of all possible mutations, allowing these empirical data to be integrated into the clinical assessment of novel rare variants 3,4 . Historically, these types of functional assays have been conducted in a serial nature, which limits scalability, and often only within a portion of the protein of interest. While there are some notable examples of whole-gene brute force saturation mutagenesis, e.g., TP535 , new more scalable experimental paradigms are being developed that allow the functional dissection of the effects of thousands of genetic mutations in parallel 6 . These approaches leverage recent advances in DNA synthesis and sequencing technologies and have proven particularly valuable in understanding the effects of mutations in cancer-associated genes 7,8 . With these issues in mind, we have developed a saturation mutagenesis approach to...

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“…PTEN is a dual specificity protein and lipid phosphatase that not only targets acidic residues in protein substrates, but more importantly, the 3-phosphate from PIP3, converting it back to PIP2 (10). PTEN signaling regulates cell division and can also direct cells to enter a natural cell death pathway when sufficient growth has taken place by inducing G1-phase cell cycle arrest through the retinoblastoma protein (11, 12).…”

Section: Genetic Alterations In the Pi3k/akt/mtor Signaling Pathway Imentioning

confidence: 99%

Genomic Rearrangements of PTEN in Prostate Cancer

Phin¹,

Moore²,

Cotter³

2013

Front. Oncol.

107

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The phosphatase and tensin homolog gene (PTEN) on chromosome 10q23.3 is a negative regulator of the PIK3/Akt survival pathway and is the most frequently deleted tumor suppressor gene in prostate cancer. Monoallelic loss of PTEN is present in up to 60% of localized prostate cancers and complete loss of PTEN in prostate cancer is linked to metastasis and androgen-independent progression. Studies on the genomic status of PTEN in prostate cancer initially used a two-color fluorescence in situ hybridization (FISH) assay for PTEN copy number detection in formalin fixed paraffin embedded tissue preparations. More recently, a four-color FISH assay containing two additional control probes flanking the PTEN locus with a lower false-positive rate was reported. Combined with the detection of other critical genomic biomarkers for prostate cancer such as ERG, androgen receptor, and MYC, the evaluation of PTEN genomic status has proven to be invaluable for patient stratification and management. Although less frequent than allelic deletions, point mutations in the gene and epigenetic silencing are also known to contribute to loss of PTEN function, and ultimately to prostate cancer initiation. Overall, it is clear that PTEN is a powerful biomarker for prostate cancer. Used as a companion diagnostic for emerging therapeutic drugs, FISH analysis of PTEN is promisingly moving human prostate cancer closer to more effective cancer management and therapies.

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Unique biochemical properties of the protein tyrosine phosphatase activity of PTEN—Demonstration of different active site structural requirements for phosphopeptide and phospholipid phosphatase activities of PTEN

Cited by 21 publications

References 32 publications

Structural mutation analysis of PTEN and its genotype‐phenotype correlations in endometriosis and cancer

Structural mutation analysis of PTEN and its genotype‐phenotype correlations in endometriosis and cancer

A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotypes relationships

Genomic Rearrangements of PTEN in Prostate Cancer

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