LINGO-1, WNK1, and EGFR: A Hypothesis

In an excellent paper Zhang and colleagues elegantly demonstrated that WNK1 interacts with LINGO-1 in regulating neurite outgrowth and growth cone collapse (1). The authors must be congratulated on discovering the role of WNK1 in the signal transduction pathways downstream to the Nogo receptor complex, which converge on RhoA.

Epidermal growth factor receptor (EGFR) activation has been shown to mediate inhibition of neurite outgrowth and growth cone collapse, and EGFR inhibition has been shown to improve axonal injury (2, 3). Interestingly, binding of epidermal growth factor (EGF) to EGFR alone was not sufficient to inhibit neurite outgrowth (2), and the mechanism by which EGFR inhibition improves axonal regeneration is yet to be determined. Notwithstanding, inter-receptor transactivation of EGFR upon activation of the Nogo receptor complex has been suggested. Also, EGFR activation has been linked to reactive astrocytosis, which inhibits axonal regeneration.

In addition, a role for EGFR in WNK1 signaling may be hypothesized. WNK1 is known to activate downstream cascades in response to physiological concentrations of EGF (4). It may be possible that anti-EGFR strategies are targeting this step of the pathway to disinhibit axonal regeneration. Recently, PirB has emerged as another high affinity receptor for myelin-based inhibitors of axonal regeneration in addition to the Nogo receptor (5), and it remains to be seen if WNK1 plays a role in PirB-induced inhibition of neurite outgrowth as well.