PMID- 34465890
OWN - NLM
STAT- MEDLINE
DCOM- 20220404
LR  - 20230206
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Print)
IS  - 1350-9047 (Linking)
VI  - 29
IP  - 1
DP  - 2022 Jan
TI  - Mechanosensitive turnover of phosphoribosyl pyrophosphate synthetases regulates 
      nucleotide metabolism.
PG  - 206-217
LID - 10.1038/s41418-021-00851-7 [doi]
AB  - Cells coordinate their behaviors with the mechanical properties of the 
      extracellular matrix (ECM). Tumor cells frequently harbor an enhanced nucleotide 
      synthesis, presumably to meet the increased demands for rapid proliferation. 
      Nevertheless, how ECM rigidity regulates nucleotide metabolism remains elusive. 
      Here we show that shift from stiff to soft matrix blunts glycolysis-derived 
      nucleotide synthesis in tumor cells. Soft ECM results in TNF receptor-associated 
      factor 2 (TRAF2)-dependent K29 ubiquitination and degradation of phosphoribosyl 
      pyrophosphate synthetase (PRPS)1/2. Recruitment of TRAF2 to PRPS1/2 requires 
      phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low 
      stiffness-activated large tumor suppressor (LATS)1/2 kinases. Further, 
      non-phosphoryable or non-ubiquitinatable PRPS1/2 mutations maintain PRPS1/2 
      expression and nucleotide synthesis at low stiffness, and promote tumor growth 
      and metastasis. Our findings demonstrate that PRPS1/2 stability and nucleotide 
      metabolism is ECM rigidity-sensitive, and thereby highlight a regulatory cascade 
      underlying mechanics-guided tumor metabolism reprogramming.
CI  - (c) 2021. The Author(s), under exclusive licence to ADMC Associazione 
      Differenziamento e Morte Cellulare.
FAU - Li, Jingyi
AU  - Li J
AD  - The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear 
      Corporation 416 Hospital, Chengdu, China.
AD  - School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 
      China.
FAU - Shao, Jichun
AU  - Shao J
AD  - The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear 
      Corporation 416 Hospital, Chengdu, China.
FAU - Zeng, Zhijun
AU  - Zeng Z
AD  - The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear 
      Corporation 416 Hospital, Chengdu, China.
FAU - He, Yumin
AU  - He Y
AD  - State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral 
      Diseases, Chinese Academy of Medical Sciences Research Unit of Oral 
      Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan 
      University, Chengdu, China.
FAU - Tang, Can
AU  - Tang C
AD  - School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 
      China.
FAU - Park, Su Hwan
AU  - Park SH
AD  - Department of Health Sciences, The Graduate School of Dong-A University, Busan, 
      Republic of Korea.
FAU - Lee, Jong-Ho
AU  - Lee JH
AD  - Department of Health Sciences, The Graduate School of Dong-A University, Busan, 
      Republic of Korea.
AD  - Department of Biological Sciences, Dong-A University, Busan, Republic of Korea.
FAU - Liu, Rui
AU  - Liu R
AUID- ORCID: 0000-0001-8757-3159
AD  - State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral 
      Diseases, Chinese Academy of Medical Sciences Research Unit of Oral 
      Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan 
      University, Chengdu, China. liurui_scu@hotmail.com.
LA  - eng
GR  - 81672674/National Natural Science Foundation of China (National Science 
      Foundation of China)/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210831
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
RN  - 0 (Nucleotides)
RN  - 7540-64-9 (Phosphoribosyl Pyrophosphate)
RN  - EC 2.7.6.1 (Ribose-Phosphate Pyrophosphokinase)
RN  - EC 6.- (Ligases)
SB  - IM
MH  - Ligases/metabolism
MH  - Nucleotides/metabolism
MH  - *Phosphoribosyl Pyrophosphate
MH  - Phosphorylation
MH  - *Ribose-Phosphate Pyrophosphokinase/genetics/metabolism
PMC - PMC8738752
COIS- The authors declare no competing interests.
EDAT- 2021/09/02 06:00
MHDA- 2022/04/05 06:00
PMCR- 2023/01/01
CRDT- 2021/09/01 07:15
PHST- 2020/12/17 00:00 [received]
PHST- 2021/08/05 00:00 [accepted]
PHST- 2021/08/02 00:00 [revised]
PHST- 2021/09/02 06:00 [pubmed]
PHST- 2022/04/05 06:00 [medline]
PHST- 2021/09/01 07:15 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.1038/s41418-021-00851-7 [pii]
AID - 851 [pii]
AID - 10.1038/s41418-021-00851-7 [doi]
PST - ppublish
SO  - Cell Death Differ. 2022 Jan;29(1):206-217. doi: 10.1038/s41418-021-00851-7. Epub 
      2021 Aug 31.