Related Experiment Video
Updated: Nov 4, 2025
07:41
Simultaneous Electrical and Mechanical Stimulation to Enhance Cells' Cardiomyogenic Potential
Published on: January 18, 2019
7.8K
MAP4K4 expression in cardiomyocytes: multiple isoforms, multiple phosphorylations and interactions with striatins
Stephen J Fuller1, Nick S Edmunds1, Liam J McGuffin1
1School of Biological Sciences, University of Reading, Whiteknights Campus, Reading RG6 2AS, U.K.
The Biochemical Journal
|May 25, 2021
Summary
The Ste/Thr kinase MAP4K4 is regulated by STRIPAK complexes in cardiomyocytes. It influences cytoskeletal organization rather than activating JNKs, challenging previous assumptions about its role in heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Cell Biology
- Signal Transduction
Background:
- Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a Ser/Thr kinase implicated in linking oxidative stress to JNKs and heart failure.
- MAP4K4 is typically regulated within striatin-interacting phosphatase and kinase (STRIPAK) complexes, where it is kept inactive by dephosphorylation.
- The precise regulation of MAP4K4 in cardiomyocytes and its specific functions remained unclear.
Purpose of the Study:
- To elucidate the regulatory mechanisms of MAP4K4 in cardiomyocytes.
- To characterize the structure and function of rat MAP4K4.
- To investigate the interaction of MAP4K4 with STRIPAK complexes and its role in cardiac signaling.
Main Methods:
- 5'-RACE and full-length sequence cloning to define the rat MAP4K4 gene.
- Expression of FLAG-MAP4K4 in HEK293 cells and cardiomyocytes.
- Treatment with calyculin A (CalA) to induce hyperphosphorylation.
- Co-immunoprecipitation to assess protein interactions.
- Computational analysis of protein-protein interactions.
- Assessment of JNK activation and myofibrillar organization.
Main Results:
- The first coding exon and full-length sequence of rat MAP4K4 were identified, revealing alternative splicing and an important C-terminal α-helix.
- Calyculin A induced MAP4K4 hyperphosphorylation, dependent on its kinase activity, affecting the activation loop and linker regions.
- MAP4K4 associated with myosin and all three striatins in cardiomyocytes, indicating STRIPAK complex integration.
- Contrary to expectations, MAP4K4 inhibited H2O2-induced JNK activation and promoted myofibrillar organization in cardiomyocytes.
Conclusions:
- MAP4K4 is regulated by STRIPAK complexes within cardiomyocytes.
- MAP4K4's function in cardiomyocytes involves cytoskeletal regulation, not JNK activation.
- These findings reframe the role of MAP4K4 in cardiac physiology and pathology.
Related Concept Videos
01:07MAPK Signaling Cascades
6.8K
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...
6.8K
01:16Calmodulin-dependent Signaling
5.5K
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
5.5K
01:29Cardiomyopathy IV: Restrictive Cardiomyopathy
149
Restrictive cardiomyopathy (RCM) is a rare heart muscle disease characterized by impaired ventricular filling due to stiffened ventricular walls, leading to significant diastolic dysfunction.EtiologyRestrictive cardiomyopathy can arise from both inherited and acquired diseases, many of which are systemic. It is categorized into four main types: infiltrative, storage, non-infiltrative, and endomyocardial diseases.Infiltrative diseases, such as amyloidosis, lead to RCM by depositing amyloid...
149
01:13Structure of Cardiac Muscles
15.6K
Cardiac muscle, or myocardium, is a specialized type of muscle found exclusively in the heart. Its unique structural and functional characteristics enable the heart to perform its vital role of pumping blood throughout the body continuously and rhythmically. The cardiac muscle cells, or cardiomyocytes, possess an endomysium and perimysium but do not have an epimysium.
Compared to skeletal muscles, cardiac muscle cells are small and mostly have a single nucleus. Additionally, they are usually...
Compared to skeletal muscles, cardiac muscle cells are small and mostly have a single nucleus. Additionally, they are usually...
15.6K