Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.1.3.16 (
calcineurin
)
17,112
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Constitutive phosphatidylinositol 3-kinase (PI3K)-AKT activation has a causal role in adult T-cell leukaemia-lymphoma (ATLL) and other cancers. ATLL cells do not harbour genetic alterations in PTEN and PI3KCA but express high levels of PTEN that is highly phosphorylated at its C-terminal tail. Here we report a mechanism for the
N-myc downstream-regulated gene 2
(
NDRG2
)-dependent regulation of PTEN phosphatase activity via the dephosphorylation of PTEN at the Ser380, Thr382 and Thr383 cluster within the C-terminal tail. We show that
NDRG2
is a PTEN-binding protein that recruits protein phosphatase 2A (
PP2A
) to PTEN. The expression of
NDRG2
is frequently downregulated in ATLL, resulting in enhanced phosphorylation of PTEN at the Ser380/Thr382/Thr383 cluster and enhanced activation of the PI3K-AKT pathway. Given the high incidence of T-cell lymphoma and other cancers in
NDRG2
-deficient mice, PI3K-AKT activation via enhanced PTEN phosphorylation may be critical for the development of cancer.
...
PMID:Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers. 2456 12
N-myc downstream-regulated gene 2
(
NDRG2
) as a tumor suppressor is frequently downregulated in human T-lymphotropic retrovirus (HTLV-1)-infected adult T-cell leukemia (ATL) and variety of cancers, and negatively regulates PI3K signaling pathways through dephosphorylation of PTEN with protein phosphatase 2A (
PP2A
). We recently identified that protein arginine methyltransferase 5 (PRMT5) is one of novel
NDRG2
binding proteins and the knockdown of PRMT5 induces cell apoptosis with degradation of several signaling molecules. To investigate how the apoptosis is induced by the knockdown PRMT5 expression, heat shock protein 90 alpha (HSP90A) was identified as a binding protein for
NDRG2
or PRMT5 by immunoprecipitation-mass analysis.
NDRG2
/
PP2A
complex inhibited arginine methyltransferase activity of PRMT5 through dephosphorylation at Serine 335 (S335); however, in
NDRG2
low
ATL-related cells, highly phosphorylated PRMT5 at S335 was mainly localized in cytoplasm with binding to HSP90A, resulting in enhancing arginine-methylation at the middle domain (R345 and R386). Since knockdown of PRMT5 expression or forced expression of HSP90A with alanine replacement of R345 or R386 induced apoptosis with the degradation of client proteins in
NDRG2
low
ATL-related and other cancer cells, we here identified that the novel arginine methylations of HSP90A are essential for maintenance of its function in
NDRG2
low
ATL and other cancer cells.
...
PMID:Novel PRMT5-mediated arginine methylations of HSP90A are essential for maintenance of HSP90A function in NDRG2
low
ATL and various cancer cells. 3176 70
N-myc downstream-regulated gene 2
(
NDRG2
) is a candidate tumor suppressor in various cancers, including adult T-cell leukemia/lymphoma (ATLL).
NDRG2
, as a stress-responsive protein, is induced by several stress-related signaling pathways and
NDRG2
negatively regulates various signal transduction pathways. Although it has not been found to function alone,
NDRG2
binds serine/threonine protein phosphatase 2A (
PP2A
), generating a complex that is involved in the regulation of various target proteins. The main function of
NDRG2
is to maintain cell homeostasis by suppressing stress-induced signal transduction; however, in cancer, genomic deletions and/or promoter methylation may inhibit the expression of
NDRG2
, resulting in enhanced tumor development via overactivated signal transduction pathways. A wide variety of tumors develop in Ndrg2-deficient mice, including T-cell lymphoma, liver, lung and other tumors, the characteristics of which are similar to those in Pten-deficient mice. In particular, PTEN is a target molecule of the
NDRG2
/
PP2A
complex, which enhances PTEN phosphatase activity by dephosphorylating residues in the PTEN C-terminal region. In ATLL cells, loss of
NDRG2
expression leads to the failed recruitment of
PP2A
to PTEN, resulting in the inactivation of PTEN phosphatase with phosphorylation, ultimately leading to the activation of PI3K/AKT. Thus,
NDRG2
, as a
PP2A
adaptor, regulates the global phosphorylation of important signaling molecules. Moreover, the downregulation of
NDRG2
expression via long-term stress-induced methylation is directly correlated with the development of ATLL and other cancers. Thus,
NDRG2
might be important for the development of stress-induced leukemia and other cancers and has become an important target for novel molecular therapies.
...
PMID:Pathophysiological significance of NDRG2 in cancer development through PP2A phosphorylation regulation. 3312 18
