Downregulation of ClC-2 by JAK2
Zohreh Hosseinzadeh1, Shefalee K Bhavsar, Florian Lang
1Department of Physiology I, University of Tübingen, Tübingen, Germany.
Summary
Janus kinase-2 (JAK2) down-regulates ClC-2 channel activity, impacting cell volume regulation. This study found JAK2 reduces ClC-2 protein in the cell membrane, affecting chloride ion (Cl-) exit.
Area of Science:
- Molecular Biology
- Cell Physiology
- Ion Channel Function
Background:
- Janus kinase-2 (JAK2) activation by cell shrinkage suggests a role in cell volume regulation.
- Small conductance chloride channels (ClC-2) are key players in cell volume regulatory mechanisms.
Purpose of the Study:
- To investigate the influence of JAK2 on the activity of ClC-2 channels.
- To determine if JAK2 modulates ClC-2 channel function and cell volume regulation.
Main Methods:
- Xenopus oocytes were used to coexpress ClC-2 with wild-type JAK2, active (V617F)JAK2, or inactive (K882E)JAK2.
- Dual electrode voltage clamp measured Cl(-) channel activity.
- Chemiluminescence and brefeldin A were used to assess channel protein abundance and membrane insertion/retrieval.
Main Results:
- Coexpression of JAK2 or (V617F)JAK2 with ClC-2 significantly decreased cell membrane conductance compared to ClC-2 alone.
- (V617F)JAK2's effect on conductance was partially reversed by the JAK2 inhibitor AG490.
- JAK2 was found to decrease ClC-2 channel protein abundance in the cell membrane, potentially by slowing insertion.
Conclusions:
- JAK2 negatively regulates ClC-2 channel activity, thereby counteracting chloride ion (Cl-) efflux.
- This JAK2-mediated down-regulation of ClC-2 activity has implications for cellular volume control mechanisms.
Related Concept Videos
01:20The JAK-STAT Signaling Pathway
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
01:15Receptor Downregulation in MVBs
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
01:22Amplifying Signals via Enzymatic Cascade
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
00:50Anaphase Promoting Complex
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
02:23Abnormal Proliferation
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
02:34Inhibition 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...