FERMT2 protein (Fermitin Family Member 2, also known as Kindlin-2 or MIG-2) is a FERM domain-containing adaptor protein encoded by the FERMT2 gene. FERMT2/Kindlin-2 is an essential integrin co-activator that links integrins to the actin cytoskeleton and mediates cell adhesion, migration, and extracellular matrix signaling. FERMT2 is a genome-wide significant risk locus for Alzheimer's disease, and emerging evidence implicates it in amyloid precursor protein (APP) trafficking, amyloid-beta production, and tau pathology.
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| Protein Name | Fermitin family homolog 2 (Kindlin-2) |
| Gene | [FERMT2](/genes/fermt2) |
| UniProt ID | [Q96AC1](https://www.uniprot.org/uniprot/Q96AC1) |
| PDB IDs | [3VIH](https://www.rcsb.org/structure/3VIH) |
| Molecular Weight | 78.4 kDa |
| Subcellular Localization | Focal adhesions, cytoplasm, cell membrane |
| Protein Family | Kindlin/Fermitin family (FERM domain proteins) |
| Associated Diseases | [Alzheimer's disease](/diseases/alzheimers-disease) |
¶ Domain Architecture
FERMT2 is a 680-amino acid protein with a split FERM (4.1-ezrin-radixin-moesin) domain:
- F0 subdomain (residues 1-92): Ubiquitin-like fold; mediates membrane targeting
- F1 subdomain (residues 93-259): Contains an inserted pleckstrin homology (PH) domain for phosphoinositide binding (PI(3,4,5)P3 and PI(3,4)P2)
- F2 subdomain (residues 260-545): Structural core of the FERM domain
- F3 subdomain (residues 546-680): Contains the integrin β-tail binding site (NPxY motif recognition); directly binds integrin β1, β2, and β3 cytoplasmic tails
FERMT2 cooperates with talin to activate integrins:
- FERMT2 F3 domain binds the membrane-distal NPxY motif of integrin β tails
- Talin FERM domain binds the membrane-proximal NPxY motif
- Together, they separate the integrin α and β transmembrane helices, switching integrins to the high-affinity extended conformation
- Active integrins bind extracellular matrix ligands and transmit outside-in signals
¶ Cell Adhesion and Migration
- Essential co-activator for integrin-mediated cell adhesion to extracellular matrix
- Required for focal adhesion assembly and maturation
- Connects integrins to the actin cytoskeleton through interactions with ILK, paxillin, and migfilin
- Knockout is embryonic lethal in mice (defective heart and vascular development)
- Expressed in neurons, astrocytes, and microglia
- Neuronal FERMT2 regulates dendritic spine morphology through integrin signaling
- Supports synaptic adhesion and plasticity at excitatory synapses
- Modulates neuronal migration during development
Recent studies reveal a direct role in AD pathogenesis:
- FERMT2 regulates APP endocytic trafficking through integrin-dependent endosomal sorting
- FERMT2 knockdown increases APP residence time in endosomes, promoting amyloidogenic processing
- FERMT2 modulates the interaction between APP and the retromer complex (VPS35/VPS26/VPS29)
FERMT2 is a genome-wide significant AD risk locus (rs17125944, p < 5×10−8):
- Risk variants reduce FERMT2 expression in the brain
- FERMT2 knockdown in neurons increases Aβ42 production by shifting APP processing toward the amyloidogenic pathway
- FERMT2 deficiency impairs APP recycling from endosomes to the cell surface
- FERMT2 also modulates tau phosphorylation through integrin-linked kinase (ILK) signaling
- Reduced FERMT2 expression correlates with faster cognitive decline in AD patients
- FERMT2 expression is reduced in AD hippocampus and entorhinal cortex
Multiple pathways through which reduced FERMT2 contributes to AD:
- Increased Aβ production: Endosomal trapping of APP enhances BACE1-mediated cleavage
- Impaired Aβ clearance: Reduced integrin-mediated microglial phagocytosis
- Tau phosphorylation: ILK hyperactivation from disrupted integrin signaling promotes tau phosphorylation
- Synaptic dysfunction: Impaired integrin-dependent synaptic plasticity and spine maintenance
- BBB disruption: FERMT2 loss in endothelial cells compromises blood-brain barrier integrity
- FERMT2 is a potential therapeutic target for AD, but as a loss-of-function risk factor, restoration strategies are needed
- Gene therapy: AAV-FERMT2 delivery to restore expression in vulnerable brain regions
- Integrin signaling modulators: Small molecules that enhance integrin activation may compensate for FERMT2 reduction
- Retromer stabilizers: R33 and similar compounds may partially compensate for FERMT2-dependent APP trafficking defects