Related Experiment Video

Updated: Aug 31, 2025

Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium
08:46

Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium

Published on: September 1, 2015

9.9K

CaMK4 overexpression in polycystic kidney disease promotes mTOR-mediated cell proliferation

Yan Zhang1,2, Emily A Daniel1,2, July Metcalf1,2

  • 1Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160-3018, USA.

Journal of Molecular Cell Biology
|August 24, 2022
PubMed

Insights

Calcium/calmodulin-dependent kinase IV (CaMK4) overactivity drives mammalian target of rapamycin (mTOR) signaling, promoting cyst growth in autosomal dominant polycystic kidney disease (ADPKD). Inhibiting CaMK4 reduces proliferation in ADPKD kidney cells.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Biochemistry

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) involves progressive kidney cyst enlargement and nephron loss.
  • Overactive mammalian target of rapamycin (mTOR) signaling contributes to ADPKD cyst growth, but its upstream activators are not fully understood.

Purpose of the Study:

  • To investigate the role of calcium/calmodulin-dependent kinase IV (CaMK4) in ADPKD pathogenesis.
  • To determine if CaMK4 contributes to mTOR activation and cyst cell proliferation in ADPKD.

Main Methods:

  • Assessed CaMK4 expression in human ADPKD kidneys and mouse models.
  • Utilized CaMK4 knockdown and pharmacologic inhibition (KN-93) in human ADPKD cells.
  • Examined the impact on mTOR signaling, cell proliferation, and in vitro cyst formation.
  • Investigated upstream regulators of CaMK4 and its interaction with the AMPK pathway.

Main Results:

  • CaMK4 is overexpressed in ADPKD kidneys.
  • CaMK4 inhibition reduced mTOR signaling, S6K phosphorylation, and ADPKD cell proliferation and cyst formation.
  • Inhibition of CaMK4 upstream regulators also decreased mTOR signaling.
  • Combined CaMK4 inhibition and metformin (AMPK activator) showed additive effects on inhibiting mTOR signaling and cyst growth.

Conclusions:

  • Increased CaMK4 expression and activity are key drivers of mTOR signaling in ADPKD.
  • CaMK4 inhibition represents a potential therapeutic strategy for ADPKD by targeting cyst cell proliferation.
Keywords:
ADPKDAMPKCaMK4CaMKKβLKB1calmodulin

More Related Videos

Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes15:43

Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes

Published on: January 7, 2013

18.2K
Use of Ultra-high Field MRI in Small Rodent Models of Polycystic Kidney Disease for In Vivo Phenotyping and Drug Monitoring07:35

Use of Ultra-high Field MRI in Small Rodent Models of Polycystic Kidney Disease for In Vivo Phenotyping and Drug Monitoring

Published on: June 23, 2015

11.6K

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.9K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.9K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.9K
M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
5.7K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.9K
cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
6.5K