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Query: EC:2.7.11.2 (
PDK1
)
2,238
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Although the treatment of brain tumors by targeting kinase-regulated macroautophagy/autophagy, is under investigation, the precise mechanism underlying autophagy initiation and its significance in glioblastoma (GBM) remains to be defined. Here, we report that PAK1 (p21 [RAC1] activated kinase 1) is significantly upregulated and promotes GBM development. The Cancer Genome Atlas analysis suggests that the oncogenic role of PAK1 in GBM is mainly associated with autophagy. Subsequent experiments demonstrate that PAK1 indeed serves as a positive modulator for hypoxia-induced autophagy in GBM. Mechanistically, hypoxia induces ELP3-mediated PAK1 acetylation at K420, which suppresses the dimerization of PAK1 and enhances its activity, thereby leading to subsequent PAK1-mediated ATG5 (autophagy related 5) phosphorylation at the T101 residue. This event not only protects ATG5 from ubiquitination-dependent degradation but also increases the affinity between the ATG12-ATG5 complex and ATG16L1 (autophagy related 16 like 1). Consequently, ELP3-dependent PAK1 (K420) acetylation and PAK1-mediated ATG5 (T101) phosphorylation are required for hypoxia-induced autophagy and brain tumorigenesis by promoting autophagosome formation. Silencing
PAK1
with shRNA or small molecule inhibitor FRAX597 potentially blocks autophagy and GBM growth. Furthermore, SIRT1-mediated PAK1-deacetylation at K420 hinders autophagy and GBM growth. Clinically, the levels of PAK1 (K420) acetylation significantly correlate with the expression of ATG5 (T101) phosphorylation in GBM patients. Together, this report uncovers that the acetylation modification and kinase activity of PAK1 plays an instrumental role in hypoxia-induced autophagy initiation and maintaining GBM growth. Therefore, PAK1 and its regulator in the autophagy pathway might represent potential therapeutic targets for GBM treatment.
Abbreviations:
3-MA: 3-methyladenine; Ac-
CoA
: acetyl coenzyme A; ATG5: autophagy related 5; ATG16L1, autophagy related 16 like 1; BafA
1
: bafilomycin A
1
; CDC42: cell division cycle 42; CGGA: Chinese Glioma Genome Atlas; CHX, cycloheximide; ELP3: elongator acetyltransferase complex subunit 3; GBM, glioblastoma; HBSS: Hanks balanced salts solution; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MAP2K1: mitogen-activated protein kinase kinase 1; MAPK14, mitogen-activated protein kinase 14; PAK1: p21 (RAC1) activated kinase 1;
PDK1
:
pyruvate dehydrogenase kinase
1; PGK1, phosphoglycerate kinase 1; PTMs: post-translational modifications; RAC1: Rac family small GTPase 1; SQSTM1: sequestosome 1; TCGA, The Cancer Genome Atlas.
...
PMID:Hypoxia-induced acetylation of PAK1 enhances autophagy and promotes brain tumorigenesis via phosphorylating ATG5. 3218 33
Charcot-Marie-Tooth (CMT) is a group of inherited diseases clinically and genetically heterogenous, characterised by length dependent degeneration of axons of the peripheral nervous system. A missense mutation (p.R158H) in the
pyruvate dehydrogenase kinase
3 gene (PDK3) has been identified as the genetic cause for an X-linked form of CMT (CMTX6) in two unrelated families. PDK3 is one of four
PDK
isoenzymes that regulate the activity of the pyruvate dehydrogenase complex (PDC). The balance between kinases (PDKs) and phosphatases (PDPs) determines the extend of oxidative decarboxylation of pyruvate to generate acetyl
CoA
, critically linking glycolysis and the energy producing Krebs cycle. We had shown the p.R158H mutation causes hyperactivity of PDK3 and CMTX6 fibroblasts show hyperphosphorylation of PDC, leading to reduced PDC activity and ATP production. In this manuscript we have generated induced pluripotent stem cells (iPSCs) by re-programming CMTX6 fibroblasts (iPSC
CMTX6
). We also have engineered an isogenic control (iPSC
isogenic
) and demonstrated that genetic correction of the p.R158H mutation reverses the CMTX6 phenotype. Patient-derived motor neurons (MN
CMTX6
) show increased phosphorylation of the PDC, energy metabolism defects and mitochondrial abnormalities, including reduced velocity of trafficking mitochondria in the affected axons. Treatment of the MN
CMTX6
with a
PDK
inhibitor reverses PDC hyperphosphorylation and the associated functional deficits founds in the patient motor neurons, demonstrating that the MN
CMTX6
and MN
isogenic
motor neurons provide an excellent neuronal system for compound screening approaches to identify drugs for the treatment of CMTX6.
...
PMID:Energy metabolism and mitochondrial defects in X-linked Charcot-Marie-Tooth (CMTX6) iPSC-derived motor neurons with the p.R158H PDK3 mutation. 3250
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