Valproic acid (VPA), the drug for
bipolar disorder and
epilepsy, has a potent ability to induce neuronal differentiation, yet comparatively little is presently known about the underlying mechanism. We previously demonstrated that
c-Jun N-terminal kinase (JNK) phosphorylation of the focal adhesion
protein paxillin mediates differentiation in N1E-115
neuroblastoma cells. Here, we show that VPA up-regulates the
neurofibromatosis type 2 (NF2)
tumor suppressor,
merlin, to regulate neurite outgrowth through the interaction with
paxillin. The inhibition of
merlin function by its knockdown or expression of
merlin harboring the Gln-538-to-Pro mutation, a naturally occurring NF2 missense mutation deficient in linking
merlin to the actin cytoskeleton, decreases VPA-induced neurite outgrowth. Importantly, the expression of
merlin by itself is not sufficient to induce neurite outgrowth, which requires co-expression with
paxillin, the binding partner of
merlin. In fact, the missense mutation Trp-60-to-Cys or Phe-62-to-Ser, that is deficient in binding to
paxillin, reduces neurite outgrowth induced by VPA. In addition, co-expression of a
paxillin construct harboring the mutation at the JNK phosphorylation site with
merlin results in blunted induction of the outgrowth. We also find that the first LIM domain of
paxillin is a major binding region with
merlin and that expression of the isolated first LIM domain blocks the effects of VPA. Furthermore, similar findings that
merlin regulates neurite outgrowth through the interaction with
paxillin have been observed in several kinds of neuronal cells. These results suggest that
merlin is an as yet unknown regulator of neurite outgrowth through the interaction with
paxillin, providing a possibly common mechanism regulating neurite formation.