Reference SummaryPapa A, Cell 2014 Apr 24;157(3):595-610

Title

 Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function.

Authors

 Papa A; Wan L; Bonora M; Salmena L; Song MS; Hobbs RM; Lunardi A; Webster K; Ng C; Newton RH; Knoblauch N; Guarnerio J; Ito K; Turka LA; Beck AH; Pinton P; Bronson RT; Wei W; Pandolfi PP

Journal

 Cell

Volume

 157

Issue

 3

Year

 2014

Pages

 595-610

Abstract

 PTEN dysfunction plays a crucial role in the pathogenesis of hereditary and sporadic cancers. Here, we show that PTEN homodimerizes and, in this active conformation, exerts lipid phosphatase activity on PtdIns(3,4,5)P3. We demonstrate that catalytically inactive cancer-associated PTEN mutants heterodimerize with wild-type PTEN and constrain its phosphatase activity in a dominant-negative manner. To study the consequences of homo- and heterodimerization of wild-type and mutant PTEN in vivo, we generated Pten knockin mice harboring two cancer-associated PTEN mutations (PtenC124S and PtenG129E). Heterozygous Pten(C124S/+) and Pten(G129E/+) cells and tissues exhibit increased sensitivity to PI3-K/Akt activation compared to wild-type and Pten(+/-) counterparts, whereas this difference is no longer apparent between Pten(C124S/-) and Pten(-/-) cells. Notably, Pten KI mice are more tumor prone and display features reminiscent of complete Pten loss. Our findings reveal that PTEN loss and PTEN mutations are not synonymous and define a working model for the function and regulation of PTEN.

Links

 J:214411 – MGI References
24766807 – National Library of Medicine/PubMed

Strain Notes

Strain Note
B6.129S1-Ptentm1Ppp/+ "All mice are on the same C57BL/6 genetic background."
B6.Cg-Ptentm3.1Ppp/+ "All mice are on the same C57BL/6 genetic background."
Early generation mice were crossed to B6.FVB-Tg(EIIa-cre)C5379Lmgd/J mice to remove a neo cassette and then to C57BL/6 to remove the cre allele.
B6.Cg-Ptentm4.1Ppp/+ "All mice are on the same C57BL/6 genetic background."
Early generation mice were crossed to B6.FVB-Tg(EIIa-cre)C5379Lmgd/J mice to remove a neo cassette and then to C57BL/6 to remove the cre allele.
C57BL/6 "All mice are on the same C57BL/6 genetic background."

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6 Adrenal gland - Medulla pheochromocytoma Adrenal gland - Medulla

0
B6.129S1-Ptentm1Ppp/+ Adrenal gland - Medulla pheochromocytoma Adrenal gland - Medulla

73.3
B6.Cg-Ptentm3.1Ppp/+ Adrenal gland - Medulla pheochromocytoma Adrenal gland - Medulla

79.3 - 85
B6.Cg-Ptentm4.1Ppp/+ Adrenal gland - Medulla pheochromocytoma Adrenal gland - Medulla

86.5 - 91.9
C57BL/6 CNS - Brain - Cerebellum hamartoma CNS - Brain - Cerebellum

0
B6.129S1-Ptentm1Ppp/+ CNS - Brain - Cerebellum hamartoma CNS - Brain - Cerebellum

0
B6.Cg-Ptentm3.1Ppp/+ CNS - Brain - Cerebellum hamartoma CNS - Brain - Cerebellum

25.9
B6.Cg-Ptentm4.1Ppp/+ CNS - Brain - Cerebellum hamartoma CNS - Brain - Cerebellum

25
C57BL/6 Gallbladder papilloma Gallbladder

0
B6.129S1-Ptentm1Ppp/+ Gallbladder papilloma Gallbladder

46.7 - 50
B6.Cg-Ptentm3.1Ppp/+ Gallbladder papilloma Gallbladder

60 - 82.8
B6.Cg-Ptentm4.1Ppp/+ Gallbladder papilloma Gallbladder

78.4 - 89.2
C57BL/6 Intestine polyp Intestine

0 - 6.25
B6.129S1-Ptentm1Ppp/+ Intestine polyp Intestine

66.7 - 83.3
B6.Cg-Ptentm3.1Ppp/+ Intestine polyp Intestine

80 - 82.8
B6.Cg-Ptentm4.1Ppp/+ Intestine polyp Intestine

83.8 - 86.5
C57BL/6 Leukocyte - Lymphocyte hyperplasia Leukocyte - Lymphocyte

0
C57BL/6 Leukocyte - Lymphocyte hyperplasia Lymph node

0 - 6.7
B6.129S1-Ptentm1Ppp/+ Leukocyte - Lymphocyte hyperplasia Leukocyte - Lymphocyte

40
B6.129S1-Ptentm1Ppp/+ Leukocyte - Lymphocyte hyperplasia Lymph node

93.3
B6.Cg-Ptentm3.1Ppp/+ Leukocyte - Lymphocyte hyperplasia Leukocyte - Lymphocyte

85.7
B6.Cg-Ptentm3.1Ppp/+ Leukocyte - Lymphocyte hyperplasia Lymph node

97.5 - 100
B6.Cg-Ptentm4.1Ppp/+ Leukocyte - Lymphocyte hyperplasia Leukocyte - Lymphocyte

85.7
B6.Cg-Ptentm4.1Ppp/+ Leukocyte - Lymphocyte hyperplasia Lymph node

97.3 - 100
C57BL/6 Liver adenoma Liver

0
B6.129S1-Ptentm1Ppp/+ Liver adenoma Liver

0
B6.Cg-Ptentm3.1Ppp/+ Liver adenoma Liver

5.0
B6.Cg-Ptentm4.1Ppp/+ Liver adenoma Liver

10.8 - 13.3
B6.Cg-Ptentm3.1Ppp/+ Lung adenoma Lung

observed
B6.129S1-Ptentm1Ppp/+ Mammary gland adenocarcinoma Mammary gland

15.6 - 24.1
B6.Cg-Ptentm3.1Ppp/+ Mammary gland adenocarcinoma Mammary gland

22.5 - 33.3
B6.Cg-Ptentm4.1Ppp/+ Mammary gland adenocarcinoma Mammary gland

24.3 - 37.5
B6.129S1-Ptentm1Ppp/+ Mammary gland hyperplasia Mammary gland

28.9
B6.Cg-Ptentm3.1Ppp/+ Mammary gland hyperplasia Mammary gland

22.5
B6.Cg-Ptentm4.1Ppp/+ Mammary gland hyperplasia Mammary gland

18.9
C57BL/6 Mammary gland lesion Mammary gland

6.25
B6.129S1-Ptentm1Ppp/+ Mammary gland lesion Mammary gland

69.0
B6.Cg-Ptentm3.1Ppp/+ Mammary gland lesion Mammary gland

66.7
B6.Cg-Ptentm4.1Ppp/+ Mammary gland lesion Mammary gland

66.7
C57BL/6 Pituitary gland adenoma Pituitary gland

0
B6.129S1-Ptentm1Ppp/+ Pituitary gland adenoma Pituitary gland

68
B6.Cg-Ptentm3.1Ppp/+ Pituitary gland adenoma Pituitary gland

55.6
B6.Cg-Ptentm4.1Ppp/+ Pituitary gland adenoma Pituitary gland

25
C57BL/6 Prostate gland adenocarcinoma Prostate gland

0
B6.129S1-Ptentm1Ppp/+ Prostate gland adenocarcinoma Prostate gland

13.3
B6.Cg-Ptentm3.1Ppp/+ Prostate gland adenocarcinoma Prostate gland

24.1
B6.Cg-Ptentm4.1Ppp/+ Prostate gland adenocarcinoma Prostate gland

13.5
C57BL/6 Prostate gland prostatic intraepithelial neoplasia (PIN) Prostate gland

6.7
B6.129S1-Ptentm1Ppp/+ Prostate gland prostatic intraepithelial neoplasia (PIN) Prostate gland

63.3
B6.Cg-Ptentm3.1Ppp/+ Prostate gland prostatic intraepithelial neoplasia (PIN) Prostate gland

62.1
B6.Cg-Ptentm4.1Ppp/+ Prostate gland prostatic intraepithelial neoplasia (PIN) Prostate gland

54.1
B6.Cg-Ptentm4.1Ppp/+ Thyroid gland adenocarcinoma Thyroid gland

8.1
C57BL/6 Thyroid gland adenoma Thyroid gland

0
B6.129S1-Ptentm1Ppp/+ Thyroid gland adenoma Thyroid gland

9.5 - 13.3
B6.Cg-Ptentm3.1Ppp/+ Thyroid gland adenoma Thyroid gland

6.9 - 39.3
B6.Cg-Ptentm4.1Ppp/+ Thyroid gland adenoma Thyroid gland

27.0 - 48.6
C57BL/6 Thyroid gland cyst Thyroid gland

0
B6.129S1-Ptentm1Ppp/+ Thyroid gland cyst Thyroid gland

50 - 61.9
B6.Cg-Ptentm3.1Ppp/+ Thyroid gland cyst Thyroid gland

39.3 - 55
B6.Cg-Ptentm4.1Ppp/+ Thyroid gland cyst Thyroid gland

45.9 - 54.1
C57BL/6 Uterus adenoma Uterus

0
B6.129S1-Ptentm1Ppp/+ Uterus adenoma Uterus

51.1
B6.Cg-Ptentm3.1Ppp/+ Uterus adenoma Uterus

57.5
B6.Cg-Ptentm4.1Ppp/+ Uterus adenoma Uterus

51.4
C57BL/6 Uterus cyst Uterus

0
B6.129S1-Ptentm1Ppp/+ Uterus cyst Uterus

31.1
B6.Cg-Ptentm3.1Ppp/+ Uterus cyst Uterus

22.5
B6.Cg-Ptentm4.1Ppp/+ Uterus cyst Uterus

21.6