PMID- 36315652
OWN - NLM
STAT- MEDLINE
DCOM- 20221205
LR  - 20231101
IS  - 1535-3907 (Electronic)
IS  - 1535-3893 (Print)
IS  - 1535-3893 (Linking)
VI  - 21
IP  - 12
DP  - 2022 Dec 2
TI  - Phosphoproteomic Analysis Defines BABAM1 as mTORC2 Downstream Effector Promoting 
      DNA Damage Response in Glioblastoma Cells.
PG  - 2893-2904
LID - 10.1021/acs.jproteome.2c00240 [doi]
AB  - Glioblastoma (GBM) is a devastating primary brain cancer with a poor prognosis. 
      GBM is associated with an abnormal mechanistic target of rapamycin (mTOR) 
      signaling pathway, consisting of two distinct kinase complexes: mTORC1 and 
      mTORC2. The complexes play critical roles in cell proliferation, survival, 
      migration, metabolism, and DNA damage response. This study investigated the 
      aberrant mTORC2 signaling pathway in GBM cells by performing quantitative 
      phosphoproteomic analysis of U87MG cells under different drug treatment 
      conditions. Interestingly, a functional analysis of phosphoproteome revealed that 
      mTORC2 inhibition might be involved in double-strand break (DSB) repair. We 
      further characterized the relationship between mTORC2 and BRISC and BRCA1-A 
      complex member 1 (BABAM1). We demonstrated that pBABAM1 at Ser29 is regulated by 
      mTORC2 to initiate DNA damage response, contributing to DNA repair and cancer 
      cell survival. Accordingly, the inactivation of mTORC2 significantly ablated 
      pBABAM1 (Ser29), reduced DNA repair activities in the nucleus, and promoted 
      apoptosis of the cancer cells. Furthermore, we also recognized that histone H2AX 
      phosphorylation at Ser139 (gammaH2AX) could be controlled by mTORC2 to repair the 
      DNA. These results provided a better understanding of the mTORC2 function in 
      oncogenic DNA damage response and might lead to specific mTORC2 treatments for 
      brain cancer patients in the future.
FAU - Kalpongnukul, Nuttiya
AU  - Kalpongnukul N
AD  - Interdisciplinary Program of Biomedical Sciences, Graduate School, Chulalongkorn 
      University, Bangkok 10330, Thailand.
AD  - Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn 
      University, Bangkok 10330, Thailand.
FAU - Bootsri, Rungnapa
AU  - Bootsri R
AD  - Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn 
      University, Bangkok 10330, Thailand.
AD  - Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, 
      Bangkok 10330, Thailand.
FAU - Wongkongkathep, Piriya
AU  - Wongkongkathep P
AD  - Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn 
      University, Bangkok 10330, Thailand.
AD  - Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, 
      Thailand.
FAU - Kaewsapsak, Pornchai
AU  - Kaewsapsak P
AD  - Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, 
      Bangkok 10330, Thailand.
AD  - Research Unit of Systems Microbiology, Faculty of Medicine, Chulalongkorn 
      University, Bangkok 10330, Thailand.
FAU - Ariyachet, Chaiyaboot
AU  - Ariyachet C
AUID- ORCID: 0000-0001-8647-7376
AD  - Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, 
      Bangkok 10330, Thailand.
AD  - Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, 
      Chulalongkorn University, Bangkok 10330, Thailand.
FAU - Pisitkun, Trairak
AU  - Pisitkun T
AUID- ORCID: 0000-0001-6677-2271
AD  - Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn 
      University, Bangkok 10330, Thailand.
AD  - Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, 
      Thailand.
FAU - Chantaravisoot, Naphat
AU  - Chantaravisoot N
AUID- ORCID: 0000-0003-3946-1798
AD  - Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn 
      University, Bangkok 10330, Thailand.
AD  - Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, 
      Bangkok 10330, Thailand.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221031
PL  - United States
TA  - J Proteome Res
JT  - Journal of proteome research
JID - 101128775
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 0 (Multiprotein Complexes)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - 0 (BABAM1 protein, human)
RN  - 0 (Adaptor Proteins, Signal Transducing)
SB  - IM
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 2/genetics/metabolism
MH  - *Glioblastoma/drug therapy
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Multiprotein Complexes/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1/genetics/metabolism
MH  - *Brain Neoplasms/metabolism
MH  - DNA Damage
MH  - Adaptor Proteins, Signal Transducing/genetics/metabolism
PMC - PMC9724709
OTO - NOTNLM
OT  - BABAM1
OT  - DNA damage response
OT  - glioblastoma
OT  - mTORC2
OT  - phosphoproteomics
COIS- The authors declare no competing financial interest.
EDAT- 2022/11/01 06:00
MHDA- 2022/12/06 06:00
PMCR- 2023/10/31
CRDT- 2022/10/31 14:42
PHST- 2022/11/01 06:00 [pubmed]
PHST- 2022/12/06 06:00 [medline]
PHST- 2022/10/31 14:42 [entrez]
PHST- 2023/10/31 00:00 [pmc-release]
AID - 10.1021/acs.jproteome.2c00240 [doi]
PST - ppublish
SO  - J Proteome Res. 2022 Dec 2;21(12):2893-2904. doi: 10.1021/acs.jproteome.2c00240. 
      Epub 2022 Oct 31.