Docking protein 6 (DOK6) selectively docks the neurotrophic signaling transduction to restrain peripheral neuropathy.
Yan GuoPan XiangXiaojiao SunWei LiuJiafeng ZhouBin YinLin HouBoqin QiangHuiliang LiPengcheng ShuXiao-Zhong PengPublished in: Signal transduction and targeted therapy (2024)
The appropriate and specific response of nerve cells to various external cues is essential for the establishment and maintenance of neural circuits, and this process requires the proper recruitment of adaptor molecules to selectively activate downstream pathways. Here, we identified that DOK6, a member of the Dok (downstream of tyrosine kinases) family, is required for the maintenance of peripheral axons, and that loss of Dok6 can cause typical peripheral neuropathy symptoms in mice, manifested as impaired sensory, abnormal posture, paw deformities, blocked nerve conduction, and dysmyelination. Furthermore, Dok6 is highly expressed in peripheral neurons but not in Schwann cells, and genetic deletion of Dok6 in peripheral neurons led to typical peripheral myelin outfolding, axon destruction, and hindered retrograde axonal transport. Specifically, DOK6 acts as an adaptor protein for selectivity-mediated neurotrophic signal transduction and retrograde transport for TrkC and Ret but not for TrkA and TrkB. DOK6 interacts with certain proteins in the trafficking machinery and controls their phosphorylation, including MAP1B, Tau and Dynein for axonal transport, and specifically activates the downstream ERK1/2 kinase pathway to maintain axonal survival and homeostasis. This finding provides new clues to potential insights into the pathogenesis and treatment of hereditary peripheral neuropathies and other degenerative diseases.
Keyphrases
- induced apoptosis
- spinal cord injury
- chemotherapy induced
- cell cycle arrest
- protein protein
- signaling pathway
- binding protein
- type diabetes
- cell death
- skeletal muscle
- physical activity
- endoplasmic reticulum stress
- metabolic syndrome
- oxidative stress
- amino acid
- insulin resistance
- depressive symptoms
- adipose tissue
- white matter
- protein kinase
- small molecule
- copy number
- climate change
- structural basis