Nuclear import of hepatic glucokinase depends upon glucokinase regulatory protein, whereas export is due to a nuclear export signal sequence in glucokinase

Hepatic glucokinase (GK) moves between the nucleus and cytoplasm in respons e to metabolic alterations. Here, using heterologous cell systems, we have found that at least two different mechanisms are involved in the intracellu lar movement of GK. In the absence of the GK regulatory protein (GKRP) GK r esides only in the cytoplasm. However, in the presence of GKRP, GK moves to the nucleus and resides there in association with this protein until chang es in the metabolic milieu prompt its release. GK does not contain a nuclea r localization signal sequence and does not enter the nucleus in a GKRP-ind ependent manner because cells treated with leptomycin B, a specific inhibit or of leucine-rich NES-dependent nuclear export, do not accumulate GR in th e nucleus. Instead, entry of GK into the nucleus appears to occur via a pig gy-back mechanism that involves binding to GKRP. Nuclear export of GK, whic h occurs after its release from GKRP, is due to a leucine-rich nuclear expo rt signal within the protein ((ELVR)-E-300-LVLLKLV310). Thus, GKRP appears to function as both a nuclear chaperone and metabolic sensor and is a criti cal component of a hepatic GK translocation cycle for regulating the activi ty of this enzyme in response to metabolic alterations.