PMID- 36002021
OWN - NLM
STAT- MEDLINE
DCOM- 20230103
LR  - 20230113
IS  - 1759-4685 (Electronic)
IS  - 1674-2788 (Print)
IS  - 1759-4685 (Linking)
VI  - 14
IP  - 7
DP  - 2022 Sep 27
TI  - CaMK4 overexpression in polycystic kidney disease promotes mTOR-mediated cell 
      proliferation.
LID - 10.1093/jmcb/mjac050 [doi]
LID - mjac050
AB  - Autosomal dominant polycystic kidney disease (ADPKD) is characterized by 
      progressive enlargement of fluid-filled cysts, causing nephron loss and a decline 
      in renal function. Mammalian target of rapamycin (mTOR) is overactive in 
      cyst-lining cells and contributes to abnormal cell proliferation and cyst 
      enlargement; however, the mechanism for mTOR stimulation remains unclear. We 
      discovered that calcium/calmodulin (CaM) dependent kinase IV (CaMK4), a 
      multifunctional kinase, is overexpressed in the kidneys of ADPKD patients and PKD 
      mouse models. In human ADPKD cells, CaMK4 knockdown reduced mTOR abundance and 
      the phosphorylation of ribosomal protein S6 kinase (S6K), a downstream target of 
      mTOR. Pharmacologic inhibition of CaMK4 with KN-93 reduced phosphorylated S6K and 
      S6 levels and inhibited cell proliferation and in vitro cyst formation of ADPKD 
      cells. Moreover, inhibition of calcium/CaM-dependent protein kinase kinase-beta and 
      CaM, two key upstream regulators of CaMK4, also decreased mTOR signaling. The 
      effects of KN-93 were independent of the liver kinase B1-adenosine 
      monophosphate-activated protein kinase (AMPK) pathway, and the combination of 
      KN-93 and metformin, an AMPK activator, had additive inhibitory effects on mTOR 
      signaling and in vitro cyst growth. Our data suggest that increased CaMK4 
      expression and activity contribute to mTOR signaling and the proliferation of 
      cystic cells of ADPKD kidneys.
CI  - (c) The Author(s) (2022). Published by Oxford University Press on behalf of Journal 
      of Molecular Cell Biology, CEMCS, CAS.
FAU - Zhang, Yan
AU  - Zhang Y
AD  - Department of Internal Medicine, University of Kansas Medical Center, Kansas 
      City, KS 66160-3018, USA.
AD  - Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas 
      City, KS 66160-3018, USA.
FAU - Daniel, Emily A
AU  - Daniel EA
AD  - Department of Internal Medicine, University of Kansas Medical Center, Kansas 
      City, KS 66160-3018, USA.
AD  - Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas 
      City, KS 66160-3018, USA.
FAU - Metcalf, July
AU  - Metcalf J
AD  - Department of Internal Medicine, University of Kansas Medical Center, Kansas 
      City, KS 66160-3018, USA.
AD  - Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas 
      City, KS 66160-3018, USA.
FAU - Dai, Yuqiao
AU  - Dai Y
AD  - Department of Internal Medicine, University of Kansas Medical Center, Kansas 
      City, KS 66160-3018, USA.
AD  - Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas 
      City, KS 66160-3018, USA.
FAU - Reif, Gail A
AU  - Reif GA
AD  - Department of Internal Medicine, University of Kansas Medical Center, Kansas 
      City, KS 66160-3018, USA.
AD  - Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas 
      City, KS 66160-3018, USA.
FAU - Wallace, Darren P
AU  - Wallace DP
AUID- ORCID: 0000-0003-4616-7669
AD  - Department of Internal Medicine, University of Kansas Medical Center, Kansas 
      City, KS 66160-3018, USA.
AD  - Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas 
      City, KS 66160-3018, USA.
AD  - Department of Molecular and Integrative Physiology, University of Kansas Medical 
      Center, Kansas City, KS 66160-3018, USA.
LA  - eng
GR  - P20 GM103418/GM/NIGMS NIH HHS/United States
GR  - R01 DK081579/DK/NIDDK NIH HHS/United States
GR  - R01DK081579/DK/NIDDK NIH HHS/United States
GR  - U54 DK126126/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Mol Cell Biol
JT  - Journal of molecular cell biology
JID - 101503669
RN  - 139298-40-1 (KN 93)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - SY7Q814VUP (Calcium)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.17 (CAMK4 protein, human)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 4)
RN  - EC 2.7.11.17 (Camk4 protein, mouse)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Humans
MH  - *Polycystic Kidney, Autosomal Dominant/metabolism
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Calcium
MH  - *Polycystic Kidney Diseases/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Kidney/metabolism
MH  - Cell Proliferation
MH  - *Cysts
MH  - Mammals
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 4
PMC - PMC9802383
OTO - NOTNLM
OT  - ADPKD
OT  - AMPK
OT  - CaMK4
OT  - CaMKKbeta
OT  - LKB1
OT  - calmodulin
EDAT- 2022/08/25 06:00
MHDA- 2023/01/04 06:00
PMCR- 2022/08/24
CRDT- 2022/08/24 18:53
PHST- 2021/11/04 00:00 [received]
PHST- 2022/06/01 00:00 [revised]
PHST- 2022/08/18 00:00 [accepted]
PHST- 2022/08/25 06:00 [pubmed]
PHST- 2023/01/04 06:00 [medline]
PHST- 2022/08/24 18:53 [entrez]
PHST- 2022/08/24 00:00 [pmc-release]
AID - 6674767 [pii]
AID - mjac050 [pii]
AID - 10.1093/jmcb/mjac050 [doi]
PST - ppublish
SO  - J Mol Cell Biol. 2022 Sep 27;14(7):mjac050. doi: 10.1093/jmcb/mjac050.