Figure 12

Proposed signal transduction pathways involved in the nuclear translocation of GAPDH. GAPDH (G in the figure) is present mainly in the cytoplasm in the presence of serum and growth factors. When cells are serum-depleted by incubation with SFM or treated with the AMPK activator AICAR, GAPDH moves to the nucleus. The re-addition of serum or growth factors to serum-depleted cells causes an export of nuclear GAPDH. An export of nuclear GAPDH requires the PI3K/Akt signal transduction pathway. Inhibition of PI3K and Akt by LY 294002 and SH-5, respectively, prevents GAPDH export and causes GAPDH accumulation in the nucleus. GAPDH translocation by serum and growth factors may be regulated via the CRM1-dependent nuclear export system, as judged by the inhibitory effect of LMB on GAPDH export. In contrast, the depletion of serum or growth factors (SFM) results in AMPK activation, which may play a role in the nuclear translocation of GAPDH. AMPK activation by AICAR via ZMP production also causes GAPDH translocation to the nucleus. AMPK inhibition by compound C or AMPK depletion by siRNA treatment prevents SFM- and AICAR-induced nuclear translocation of GAPDH. The inhibition of ZMP production from AICAR by the adenosine kinase inhibitor 5'-ITC reduces the AICAR-induced nuclear accumulation of GAPDH.