| Property | Value | [1] |
|----------|-------| [2] |
| Gene Symbol | MST4 |
| Full Name | Serine/Threonine-Protein Kinase MST4 |
| Chromosomal Location | Xq26.2 |
| NCBI Gene ID | 100533180 |
| OMIM ID | 300254 |
| Ensembl ID | ENSG00000101126 |
| UniProt ID | Q9P289 |
| Encoded Protein | Serine/threonine-protein kinase MST4 |
| Associated Diseases | Alzheimer's Disease (risk factor), Autoinflammatory Disease, Colorectal Cancer |
MST4 (Serine/Threonine-Protein Kinase MST4) is a human gene located on chromosome Xq26.2 that encodes a member of the sterile 20-like serine/threonine protein kinase family, which is part of the larger Hippo signaling pathway. Also known as MST4 (Mammalian Sterile 20-like Kinase 4) or STK26, this protein plays critical roles in cell proliferation, survival, migration, and tissue homeostasis. Originally characterized for its oncogenic potential in cancer biology, emerging research has revealed important functions in neuronal systems and neurodegenerative disease pathogenesis.
The protein is a central component of the STRIPAK complex (Striatin-interacting phosphatase and kinase), a highly conserved signaling hub that integrates environmental cues to regulate cell death, autophagy, cytoskeletal dynamics, and immune responses. This connection to fundamental cellular processes positions MST4 as a protein of significant interest in understanding Alzheimer's Disease and Parkinson's Disease pathogenesis.
The MST4 gene spans approximately 32 kb on chromosome Xq26.2. The gene comprises 13 exons that encode a 436-amino acid protein with a molecular weight of approximately 48 kDa.
MST4 belongs to the MST/STS family (Mammalian Sterile 20-like Kinases), which includes:
The kinase domain shows high conservation across species, reflecting fundamental roles in cell growth regulation.
MST4 possesses the canonical serine/threonine kinase structure:
The protein adopts an active conformation when phosphorylated at:
MST4 phosphorylates numerous substrates involved in diverse cellular processes:
| Substrate | Function | Reference |
|---|---|---|
| PI3K (p85) | Cell survival signaling | [3] |
| LKB1 | Energy sensing | [4] |
| TAOK1/2 | Cytoskeletal regulation | [5] |
| MOB1 | Hippo pathway coordination | [6] |
| AMPK | Metabolic regulation | [4:1] |
MST4 is a core component of the STRIPAK complex, a macromolecular signaling assembly comprising:
This complex serves as a signal integration hub that:
MST4 regulates cell cycle progression through multiple mechanisms:
Through its position in the STRIPAK complex, MST4 integrates pro-survival and pro-death signals:
MST4 plays essential roles in cytoskeletal dynamics through:
As demonstrated in [1:1], MST4 modulates immune cell function:
MST4 maintains tissue barrier function through:
MST4 has emerged as a protein of interest in Alzheimer's Disease pathogenesis through multiple mechanisms:
Neuroinflammation [7]:
Neuronal survival:
Autophagy dysregulation [5:1]:
Mitochondrial dysfunction [8]:
Targeting MST4 in AD may offer several benefits:
While less studied, MST4 may contribute to Parkinson's Disease through:
MST4 variants affect immune function and predispose to:
As characterized in [2:1], MST4 shows oncogenic potential:
MST4 shows broad expression across tissues:
| Tissue | Expression Level | Notable Regions |
|---|---|---|
| Brain | High | Cortex, hippocampus, cerebellum, basal ganglia |
| Immune system | High | T cells, B cells, macrophages, dendritic cells |
| Epithelial | Moderate-high | Intestine, lung, breast |
| Heart | Moderate | Cardiac myocytes |
| Liver | Moderate | Hepatocytes |
| Muscle | Low-moderate | Skeletal muscle |
Within the central nervous system, MST4 is expressed in:
MST4 exhibits dynamic subcellular distribution:
MST4 connects to the Hippo signaling pathway through:
MST4 → MOB1 → LATS1/2 → YAP/TAZ inhibition
↓
Cell growth control
This axis is critical for:
As described in [3:1], MST4 directly phosphorylates PI3K p85:
MST4 interacts with the MAPK pathway:
MST4 expression may serve as:
Current therapeutic approaches include:
Kinase inhibitors [9:1]:
Activation strategies (for neurodegeneration):
Combination therapies:
Key questions remain regarding MST4 in neurodegeneration:
MST4 participates in numerous protein interactions:
| Interactor | Interaction Type | Function |
|---|---|---|
| STRN3 | Structural | STRIPAK complex scaffold |
| PPP2R1A | Enzymatic | PP2A phosphatase subunit |
| MST3/STK24 | Homologous | Kinase dimerization |
| MOB1 | Substrate | Hippo pathway adapter |
| CCM2 | Structural | Complex anchoring |
| TAOK1 | Enzymatic | Upstream activation |
MST4 genetically interacts with:
Morrow et al. MST4 in inflammation (2015). 2015. ↩︎ ↩︎
Lin et al. MST4 and cancer (2010). 2010. ↩︎ ↩︎
Hwang et al. MST4 phosphorylates PI3K in cell survival. 2011. ↩︎ ↩︎
Fang et al. STRIPAK complex in neuronal development. 2019. ↩︎ ↩︎
Gu et al. MST4 in autophagy regulation. 2018. ↩︎ ↩︎
Chen et al. Hippo pathway crosstalk with MST4. 2019. ↩︎
Liu et al. MST4 and neuroinflammation in AD. 2020. ↩︎
Zhang et al. MST4 regulates mitochondrial dynamics in neurons. 2021. ↩︎
Yu et al. MST4 kinase inhibitors in disease therapy. 2022. ↩︎ ↩︎