WDR62 mediates TNFα-dependent JNK activation via TRAF2-MLK3 axis

Area of Science:

• Cellular Biology
• Molecular Biology
• Signal Transduction

Background:

• Mitogen-activated protein kinases (MAPKs) regulate diverse cellular functions.
• MAPK cascades involve sequential kinase activations, often facilitated by scaffold proteins.
• WD repeat domain 62 (WDR62) is identified as a scaffold protein for c-Jun N-terminal kinase (JNK).

Purpose of the Study:

• To investigate the role of WDR62 in JNK signaling pathways.
• To elucidate the function of WDR62 in cellular processes, particularly in cancer cells.
• To determine WDR62's involvement in TNFα-mediated signaling.

Main Methods:

• CRISPR/Cas9 and short hairpin RNA (shRNA) were used to create WDR62 loss-of-function models in MDA-MB-231 cells.
• JNK signaling pathway activation was analyzed in both growing and stressed cellular conditions.
• Cellular responses, including cell death, were assessed following TNFα stimulation.

Main Results:

• WDR62 maintains basal c-Jun expression in growing cells.
• WDR62 specifically mediates TNFα-dependent JNK activation by interacting with TRAF2 and MLK3.
• WDR62-deficient cells exhibit enhanced resistance to TNFα-induced apoptosis.
• This mechanism is conserved across different human cell lines (HCT116, HeLa).

Conclusions:

• WDR62 is essential for basal c-Jun expression and TNFα-induced JNK activation.
• WDR62 acts as a critical coordinator of the TNFα receptor signaling pathway to JNK.
• WDR62 plays a significant role in regulating cell death pathways, impacting cancer cell survival.