TAFA2

TAFA2 is a secreted neurokine that acts as a neurotrophic factor essential for neuronal survival and as a paracrine modulator of cell migration and inflammation (PMID:30137205, PMID:37944639). In the brain, TAFA2 suppresses neuronal apoptosis by binding directly to the lectin-like domain of the adhesion GPCR ADGRL1 (latrophilin-1), activating cAMP/PKA/CREB/BCL2 signaling; deletion of the lectin domain or ADGRL1 knockout abolishes its anti-apoptotic effect (PMID:37944639). Consistent with this pro-survival role, TAFA2 loss in knockout mice produces severe neuronal reduction and apoptosis accompanied by downregulation of PI3K/Akt and MAPK/Erk signaling and reduced CREB target gene expression (PMID:30137205). Beyond the nervous system, TAFA2 drives human skeletal stem cell migration and proliferation through Rac1-p38 pathway activation, with IL-1β acting as an upstream inducer during fracture healing (PMID:30485583). Neuron-derived TAFA2 also engages the chemokine receptor CCR2 to promote macrophage activation and aggravate liver ischaemia-reperfusion injury, an effect lost in Ccr2-deficient macrophages (PMID:40058705).

1. 2018 Medium

   Establishing whether TAFA2 has a non-redundant physiological role, loss-of-function in mice defined it as a neurotrophic factor required for neuronal survival.

   Evidence Knockout mouse with behavioral testing, apoptosis immunohistochemistry, and Western blot of survival pathway components

   PMID:30137205

   Open questions at the time

   • Did not identify the receptor mediating the survival signal
   • Pathway readouts correlative without direct receptor linkage
2. 2018 Medium

   Extending TAFA2's role beyond neurons, it was shown to drive skeletal stem cell migration and proliferation, linking it to tissue repair.

   Evidence In vitro migration assays, Rac1 activity assay, p38 inhibition, in vivo femoral fracture model, and patient serum measurement

   PMID:30485583

   Open questions at the time

   • Receptor on skeletal stem cells not identified
   • Mechanism connecting IL-1β induction to TAFA2 secretion unresolved
3. 2023 High

   Identifying the long-missing receptor, TAFA2 was shown to bind ADGRL1's lectin-like domain and signal through cAMP/PKA/CREB/BCL2 to block neuronal apoptosis.

   Evidence Co-IP plus quantitative mass spectrometry in V5 knockin brain lysates, pull-down, ADGRL1 knockout and lectin-domain deletion functional analysis

   PMID:37944639

   Open questions at the time

   • Structural basis of the lectin-domain interaction not resolved
   • Relationship between ADGRL1 signaling and the earlier PI3K/Akt-MAPK readouts not reconciled
4. 2025 Medium

   Revealing a pro-inflammatory function, neuron-derived TAFA2 was shown to engage CCR2 to activate macrophages and worsen liver injury.

   Evidence FLAG-tagged TAFA2 Co-IP identifying CCR2, macrophage RNA-seq, Ccr2 knockout rescue, in vivo ablation and neuron-specific knockdown, single-cell sequencing

   PMID:40058705

   Open questions at the time

   • CCR2 binding shown by Co-IP without reciprocal structural validation
   • How a neuronal secreted factor reaches liver macrophages not fully defined

• It remains unresolved how TAFA2 selects among its distinct receptors (ADGRL1 versus CCR2) in different tissues and whether a single receptor mediates its skeletal stem cell effects.
• No receptor assigned for the skeletal stem cell Rac1-p38 response
• Determinants of context-specific receptor engagement unknown