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    1. karim2001khoury 19 Feb 2026
      Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization

      [Paper-level Aggregated] PMCID: PMC5491373

      Evidence Type(s): Functional, Oncogenic, Predictive, Prognostic

      Justification: Functional: The text discusses how mutations L320S and T277A affect PTEN's enzymatic activity and its ability to suppress AKT phosphorylation, indicating a functional impact on PTEN's role in signaling pathways. Oncogenic: The mutations L320S and T277A are associated with a loss of PTEN function, which is critical in cancer biology, as PTEN is a tumor suppressor and its inactivation can lead to tumorigenesis. Predictive: The study suggests that specific mutations in PTEN can predict changes in protein stability and localization, which may influence the outcome of therapies targeting PTEN-related pathways. Prognostic: The presence of mutations like L320S and T277A in PTEN may serve as prognostic markers for cancer progression, given their impact on PTEN's function and localization, which are crucial for tumor suppression.

      Gene→Variant (gene-first): PTEN(5728):C124S GAPDH(2597):K13 GAPDH(2597):K13R NEDD4(4734):L320S PIK3R1(5295):F273 PIK3R1(5295):F273A PIK3R1(5295):F273L NEDD4(4734):L320 NEDD4(4734):L320F PTEN(5728):T277A PTEN(5728):K48R NEDD4(4734):L320A NEDD4(4734):L320D NEDD4(4734):L320E PTEN(5728):S370 PTEN(5728):S370A PTEN(5728):T366 PTEN(5728):T366A PTEN(5728):T319 PTEN(5728):T319A PTEN(5728):T321 PTEN(5728):T321A PTEN(5728):Lys48

      Genes: PTEN(5728) GAPDH(2597) NEDD4(4734) PIK3R1(5295)

      Variants: C124S K13 K13R L320S F273 F273A F273L L320 L320F T277A K48R L320A L320D L320E S370 S370A T366 T366A T319 T319A T321 T321A Lys48

      CIViC paper-level aggregated PMC5491373
    2. karim2001khoury 19 Feb 2026
      To determine if a lysine residue is necessary for the nuclear localization of PTEN on ubiquitinK48R expression, we tested lysine residues, K13, K254 and K289, and a cluster of five lysines (K260, K263, K266, K267, K269)

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 31

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the substitution of the lysine residue K13 alters the nuclear localization of PTEN, indicating a change in molecular function related to protein activity and localization.

      Gene→Variant (gene-first): 2597:K13

      Genes: 2597

      Variants: K13

      CIViC paragraph-level PMC5491373 Functional
    3. karim2001khoury 19 Feb 2026
      We also tested the effect of co-expression of PTENL320S-GFP and ubiquitin or ubiquitinK48R instead of expression of PTEN-ubiquitin fusion proteins. Intriguingly, in the presence of ubiquitinK48R, PTENL320S-GFP showed str

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 30

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the K48R mutation alters the molecular function of ubiquitin, affecting the localization and abundance of PTENL320S-GFP, indicating a change in biochemical activity.

      Gene→Variant (gene-first): 5728:K48R

      Genes: 5728

      Variants: K48R

      CIViC paragraph-level PMC5491373 Functional
    4. karim2001khoury 19 Feb 2026
      We then tested whether the C-terminal ubiquitin tag can rescue the nuclear localization defect of PTENL320S. We found that PTENL320S,A4-Ub-GFP significantly accumulated in the nucleus (Figures 7a and b). To determine whe

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 29

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variant Lys48 affects the molecular function of PTENL320S by influencing its nuclear localization, indicating a change in biochemical activity related to polyubiquitination.

      Gene→Variant (gene-first): 5728:Lys48

      Genes: 5728

      Variants: Lys48

      CIViC paragraph-level PMC5491373 Functional
    5. karim2001khoury 19 Feb 2026
      To further analyse the conformations of PTENT277A and PTENL320S, we measured the intramolecular interaction between the membrane-binding regulatory interface and the phosphorylated C-terminal tail of PTEN. In this assay,

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 26

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants PTENT277A and PTENL320S alter the ability of the protein to interact with the C-terminal tail, indicating a change in molecular function.

      Gene→Variant (gene-first): 4734:L320S 5728:T277A

      Genes: 4734 5728

      Variants: L320S T277A

      CIViC paragraph-level PMC5491373 Functional
    6. karim2001khoury 19 Feb 2026
      T277A and L320S inhibit the membrane-bound regulatory interface from interacting with the C-terminus

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 25

      Evidence Type(s): Functional

      Justification: Functional: The passage indicates that the L320S variant alters the interaction of a protein at the membrane-bound regulatory interface, suggesting a change in molecular function.

      Gene→Variant (gene-first): 4734:L320S

      Genes: 4734

      Variants: L320S

      CIViC paragraph-level PMC5491373 Functional
    7. karim2001khoury 19 Feb 2026
      To determine whether the altered protein conformations of PTENT277A and PTENL320S change the ubiquitination of PTEN, we co-expressed HA-ubiquitin with various GFP-PTEN constructs. GFP fusions were immunoprecipitated and

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 24

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants PTENT277A and PTENL320S alter the ubiquitination of the PTEN protein, indicating a change in molecular function related to protein stability.

      Gene→Variant (gene-first): 4734:L320S 5728:T277A

      Genes: 4734 5728

      Variants: L320S T277A

      CIViC paragraph-level PMC5491373 Functional
    8. karim2001khoury 19 Feb 2026
      To determine the effect of L320S and T277A on the protein conformation and folding of PTEN, we performed a trypsin digestion assay. We immunopurified PTENWT-GFP, PTENA4-GFP, PTENT277A-GFP and PTENL320S-GFP from HEK293T c

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 23

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants L320S and T277A alter the protein conformation and folding of PTEN, indicating a change in molecular function as demonstrated by the trypsin digestion assay.

      Gene→Variant (gene-first): 4734:L320S 5728:T277A

      Genes: 4734 5728

      Variants: L320S T277A

      CIViC paragraph-level PMC5491373 Functional
    9. karim2001khoury 19 Feb 2026
      The crystal structure of PTEN has shown that F273 interacts with L320. We hypothesize that the interactions with this amino acid is necessary to stabilize PTEN conformation (Figure 5f). We found that an F273A mutation sh

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 22

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the F273 and L320 variants interact and affect the localization and conformation of PTEN, indicating that these variants alter molecular function.

      Gene→Variant (gene-first): 5295:F273 5295:F273A 5295:F273L 4734:L320 4734:L320F 4734:L320S

      Genes: 5295 4734

      Variants: F273 F273A F273L L320 L320F L320S

      CIViC paragraph-level PMC5491373 Functional
    10. karim2001khoury 19 Feb 2026
      T277A and L320S open the conformation of PTEN and promote ubiquitination

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 21

      Evidence Type(s): Functional

      Justification: Functional: The passage indicates that the variants T277A and L320S alter the conformation of PTEN and promote ubiquitination, which suggests a change in molecular function.

      Gene→Variant (gene-first): 4734:L320S 5728:T277A

      Genes: 4734 5728

      Variants: L320S T277A

      CIViC paragraph-level PMC5491373 Functional
    11. karim2001khoury 19 Feb 2026
      We then tested whether L320S affects phosphorylation at other sites on PTEN. Two residues next to L320S, T319 and T321, have reportedly been phosphorylated by RhoA-associated kinase (ROCK) to promote PTEN membrane target

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 20

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the mutations T319A and T321A do not enhance protein stability or membrane localization of PTENL320S, indicating that these variants alter molecular function related to protein activity and localization.

      Gene→Variant (gene-first): 4734:L320S 5728:T319 5728:T319A 5728:T321 5728:T321A

      Genes: 4734 5728

      Variants: L320S T319 T319A T321 T321A

      CIViC paragraph-level PMC5491373 Functional
    12. karim2001khoury 19 Feb 2026
      Protein phosphorylation prediction analysis suggested that the substitution of L320 to S creates a new potential phosphorylation site (Supplementary Figure S2). We tested whether changing L320 to phospho-mimetic (L320D o

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 19

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the substitution of L320 to S affects the molecular function of PTEN, specifically its stability, localization, and phosphorylation status, indicating a change in biochemical function.

      Gene→Variant (gene-first): 4734:L320 4734:L320A 4734:L320D 4734:L320E 4734:L320S

      Genes: 4734

      Variants: L320 L320A L320D L320E L320S

      CIViC paragraph-level PMC5491373 Functional
    13. karim2001khoury 19 Feb 2026
      The recruitment of PTEN to the plasma membrane is crucial for PTEN activity. To determine the impact of the T277A and L320S mutations on PTEN membrane localization, we introduced T277A into PTENA4, PTENK13R,A4 and ePTEN,

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the T277A and L320S mutations alter the molecular function of PTEN by blocking its membrane localization and decreasing its ability to reduce AKT phosphorylation, indicating a change in biochemical activity. Oncogenic: The passage suggests that the nuclear localization defects caused by the T277A and L320S mutations could affect PTEN function in suppressing tumor formation, indicating that these mutations contribute to tumor development or progression.

      Gene→Variant (gene-first): 2597:K13R 4734:L320S 5728:T277A

      Genes: 2597 4734 5728

      Variants: K13R L320S T277A

      CIViC paragraph-level PMC5491373 Functional Oncogenic
    14. karim2001khoury 19 Feb 2026
      L320S and T277A mutations block PTEN membrane and nuclear localization

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 15

      Evidence Type(s): Functional

      Justification: Functional: The passage indicates that the L320S and T277A mutations alter the localization of the PTEN protein, which is a change in molecular function.

      Gene→Variant (gene-first): 4734:L320S 5728:T277A

      Genes: 4734 5728

      Variants: L320S T277A

      CIViC paragraph-level PMC5491373 Functional
    15. karim2001khoury 19 Feb 2026
      It has been shown that phosphorylation of PTEN at T366 or S370 destabilizes the protein. To determine whether blocking phosphorylation at these two sites increases the stability of PTENL320S, we created PTENL320S,T366A a

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how specific phosphorylation events at the T366 and S370 sites affect the stability of the PTEN protein, indicating that these variants alter molecular function.

      Gene→Variant (gene-first): 4734:L320S 5728:S370 5728:S370A 5728:T366 5728:T366A

      Genes: 4734 5728

      Variants: L320S S370 S370A T366 T366A

      CIViC paragraph-level PMC5491373 Functional
    16. karim2001khoury 19 Feb 2026
      To determine the mechanism that decreases the stability of PTENL320S in greater detail, we combined L320S with mutations that are known to increase PTEN stability. We introduced K13R, which has been shown to block ubiqui

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the L320S variant decreases the stability of PTEN and its interactions with the plasma membrane, indicating an alteration in molecular function. Oncogenic: The context of the passage suggests that the variants, particularly L320S, contribute to tumor development or progression by affecting PTEN stability and function, which is relevant in cancer biology.

      Gene→Variant (gene-first): 5728:C124S 2597:K13 2597:K13R 4734:L320S

      Genes: 5728 2597 4734

      Variants: C124S K13 K13R L320S

      CIViC paragraph-level PMC5491373 Functional Oncogenic
    17. karim2001khoury 19 Feb 2026
      To test whether ectopic expression of PTEN can suppress PIP3 signalling in patient-derived GBM cells, we introduced PTENWT-GFP into GBM 651 (which expressed PTENL320S), GBM 965 (which expressed no PTEN proteins) and GBM

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the PTEN variants L320S and T277A alter the molecular function of PTEN, specifically its ability to suppress AKT phosphorylation and inhibit cell migration and proliferation. Oncogenic: The variants PTENL320S and PTENT277A are implicated in decreased activity to suppress key signaling pathways and cellular behaviors associated with tumor development and progression, indicating their role in oncogenesis.

      Gene→Variant (gene-first): 4734:L320S 5728:T277A

      Genes: 4734 5728

      Variants: L320S T277A

      CIViC paragraph-level PMC5491373 Functional Oncogenic
    18. karim2001khoury 19 Feb 2026
      Because most cancer-associated mutations in PTEN abolish its essential phosphatase activity, we first tested whether L320S and T277A affect enzymatic activity. We immunopurified GFP fused to PTENL320S and PTENT277A, wild

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 6

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants L320S and T277A were tested for their effect on enzymatic activity, specifically lipid phosphatase activity, indicating that they alter molecular function.

      Gene→Variant (gene-first): 4734:L320S 5728:T277A

      Genes: 4734 5728

      Variants: L320S T277A

      CIViC paragraph-level PMC5491373 Functional
    19. karim2001khoury 19 Feb 2026
      We found two cells, GBMs 651 and 276, each of which contained a previously uncharacterized point mutation in the PTEN coding region. The former carried L320S while the latter carried T277A. Both mutant proteins had decre

      [Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the L320S and T277A mutations in PTEN alter the steady state levels of the proteins and their localization, indicating a change in molecular function. Oncogenic: The context suggests that the mutations contribute to the alteration of PTEN function, which is implicated in tumor development or progression.

      Gene→Variant (gene-first): 4734:L320S 5728:T277A

      Genes: 4734 5728

      Variants: L320S T277A

      CIViC paragraph-level PMC5491373 Functional Oncogenic
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    pmc.ncbi.nlm.nih.gov/articles/PMC5491373/pdf/onc2016493a.pdf