Phosphorylation of the PTEN Tail Regulates Protein Stability and Function

ABSTRACT The PTEN gene is a tumor suppressor localized in the frequently altered chromosomal region 10q23. The tumor suppressor function of the PTEN protein (PTEN) has been linked to its ability to dephosphorylate the lipid second-messenger phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate and, by doing so, to antagonize the phosphoinositide 3-kinase pathway. The PTEN protein consists of an amino-terminal phosphatase domain, a lipid binding C2 domain, and a 50-amino-acid C-terminal domain (the “tail”) of unknown function. A number of studies have shown that the tail is dispensable for both phosphatase activity and blocking cell growth. Here, we show that the PTEN tail is necessary for maintaining protein stability and that it also acts to inhibit PTEN function. Thus, removing the tail results in a loss of stability but does not result in a loss of function because the resultant protein is more active. Furthermore, tail-dependent regulation of stability and activity is linked to the phosphorylation of three residues (S380, T382, and T383) within the tail. Therefore, the tail is likely to mediate the regulation of PTEN function through phosphorylation.

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Rak Functions as a Tumor Suppressor by Regulating PTEN Protein Stability and Function

Cancer Cell ◽

10.1016/j.ccr.2009.02.012 ◽

2009 ◽

Vol 15 (4) ◽

pp. 304-314 ◽

Cited By ~ 131

Author(s):

Eun-Kyoung Yim ◽

Guang Peng ◽

Hui Dai ◽

Ruozhen Hu ◽

Kaiyi Li ◽

...

Keyword(s):

Tumor Suppressor ◽

Protein Stability ◽

Pten Protein ◽

And Function

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Identification of novel effectors of invasive cell growth downstream of phosphoinositide 3-kinase

Biochemical Society Transactions ◽

10.1042/bst0320355 ◽

2004 ◽

Vol 32 (2) ◽

pp. 355-359 ◽

Cited By ~ 4

Author(s):

J. Kaufmann ◽

G. Pronk ◽

K. Giese ◽

A. Klippel

Keyword(s):

Cell Growth ◽

Tumour Suppressor ◽

Growth Potential ◽

Loss Of Function ◽

Suppressor Function ◽

Tumour Suppressor Function ◽

Novel Approach ◽

Phosphoinositide 3 Kinase ◽

Invasive Cell ◽

Kinase Pathway

Conventional approaches to identifying cancer targets are complicated by the chromosomal instability of tumour cells, and typically result in a large number of differentially expressed candidate genes with uncertain disease relevance. Here we present a novel approach which aims to elucidate the molecular changes that are induced after loss of tumour suppressor function. Using gene silencing tools, we mimic the loss of tumour suppressor function to identify key regulators of tumour initiation and progression. Loss of function of the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) correlates with increased invasive cell growth due to the resulting chronic activation of the PI 3-kinase (phosphoinositide 3-kinase) pathway. Induced activation of PI 3-kinase either by inhibiting PTEN expression or by using p110*, a constitutively active PI 3-kinase, increased signalling and the invasive growth potential of cells. Using this unbiased approach we have identified novel downstream effectors of PI 3-kinase/PTEN signalling that mediate the behaviour of cells with a hyperactive PI 3-kinase pathway. These molecules represent candidate targets for therapeutic intervention in patients with PTEN-deficient tumours.

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Mutations In PIK3C2A Cause Syndromic Short Stature, Skeletal Abnormalities, and Cataracts Associated With Ciliary Dysfunction

10.1101/488411 ◽

2018 ◽

Cited By ~ 1

Author(s):

Dov Tiosano ◽

Hagit Baris Feldman ◽

Anlu Chen ◽

Marrit M. Hitzert ◽

Markus Schueler ◽

...

Keyword(s):

Short Stature ◽

Critical Role ◽

Class Ii ◽

Molecular Data ◽

Loss Of Function ◽

Skeletal Abnormalities ◽

Cilia Formation ◽

Phosphoinositide 3 Kinase ◽

And Function

AbstractPIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.

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Recurrent SETD2 mutation in NPM1-mutated acute myeloid leukemia

Biomarker Research ◽

10.1186/s40364-020-00243-y ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Jiewen Sun ◽

Wenjuan Yu ◽

Xiang Zhang

Keyword(s):

Acute Myeloid Leukemia ◽

Tumor Suppressor ◽

Cell Line ◽

Myeloid Leukemia ◽

Functional Study ◽

Loss Of Function ◽

Direct Target ◽

And Function ◽

Acute Myeloid

Abstract SETD2 is the only methyltransferase for H3K36me3, and our previous study has firstly demonstrated that it functioned as one tumor suppressor in hematopoiesis. Consistent with it, SETD2 mutation, which led to its loss of function, was identified in AML. However, the distribution and function of SETD2 mutation in AML remained largely unknown. Herein, we integrated SETD2-mutated AML cases from our center and literature reports, and found that NPM1 mutation was the most common concomitant genetic alteration with SETD2 mutation in AML, with its frequency even higher than MLL rearrangement and AML1-ETO. Though this result indicated the cooperation of SETD2 and NPM1 mutations in leukemogenesis, our functional study showed that SETD2 was required for the proliferation of NPM1-mutated AML cell line OCI-AML3, but not MLL-rearranged AML cell line THP-1, via maintaining its direct target NPM1 expression, which was just opposite to its role of tumor suppressor. Therefore, we speculated that SETD2 possibly had two different faces in distinct subtypes and stages of AML.

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Temperature-sensitive mutants of p16CDKN2 associated with familial melanoma.

Molecular and Cellular Biology ◽

10.1128/mcb.16.7.3844 ◽

1996 ◽

Vol 16 (7) ◽

pp. 3844-3852 ◽

Cited By ~ 66

Author(s):

D Parry ◽

G Peters

Keyword(s):

Tumor Suppressor ◽

Premature Termination ◽

Kinase Assay ◽

Temperature Sensitive ◽

Loss Of Function ◽

Altered Expression ◽

Familial Predisposition ◽

Familial Melanoma ◽

Amino Terminal ◽

Wide Range

Altered expression or function of the p16CDKN2 tumor suppressor gene on chromosome 9p21 occurs in a wide range of human tumors, and mutations in the gene have been shown to segregate with familial predisposition to malignant melanoma. We have used a variety of assays to examine the functional properties of tumor-associated alleles, including eight premature termination mutants, eight missense mutants, and three isoforms of p16 initiated at different amino-terminal methionine codons. The amino- and carboxy-terminal domains of the protein, outside the ankyrin-like repeats, appeared to be dispensable, but the majority of the premature termination mutations led to loss of function. Of the missense mutations tested, four displayed clear loss of function whereas two behaved like the wild type under all conditions tested. The remaining two mutations, a G-to-W mutation at position 101 (Gl01W) and V126D, both of which are associated with familial melanoma, were found to be temperature sensitive for binding to Cdk4 and Cdk6 in vitro, for inhibiting cyclin D1-Cdk4 in a reconstituted pRb-kinase assay, and for increasing the proportion of G1-phase cells following transfection. These findings clarify previous disparities and argue strongly that p16CDKN2 is a bona fide tumor suppressor associated with familial melanoma.

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