promotes the coupling of glycolysis to mitochondrial oxidative phosphorylation, which greatly enhances ATP production to meet the cell’s energy demands. Specifically, HK2 binds VDAC to trigger opening of the channel and release mitochondrial ATP to further fuel the glycolytic process. Another critical function for OMM-bound HK2 is mediation of cell survival. Activation of Akt kinase maintains HK2-VDAC coupling, which subsequently prevents cytochrome c release and apoptosis, though the exact mechanism remains to be confirmed. One model proposes that HK2 competes with the pro-apoptotic proteins BAX to bind VDAC, and in the absence of HK2, BAX induces cytochrome c release. In fact, there is evidence that HK2 restricts BAX and BAK oligomerization and binding to the OMM. In a similar mechanism, the pro-apoptotic creatine kinase binds and opens VDAC in the absence of HK2. An alternative model proposes the opposite, that HK2 regulates binding of the anti-apoptotic protein Bcl-Xl to VDAC. In particular, HK2 is ubiquitously expressed in tissues, though it is majorly found in muscle and adipose tissue. In cardiac and skeletal muscle, HK2 can be found bound to both the mitochondrial and sarcoplasmic membrane. HK2 gene expression is regulated by a phosphatidylinositol 3-kinaselp70 S6 protein kinase-dependent pathway and can be induced by factors such as insulin, hypoxia, cold temperatures, and exercise. Its inducible expression indicates its adaptive role in metabolic responses to changes in the cellular environment. Clinical significance Cancer HK2 is highly expressed in several cancers, including breast cancer and colon cancer. Its role in coupling ATP from oxidative phosphorylation to the rate-limiting step of glycolysis may help drive the tumor cells’ growth. Notably, inhibition of HK2 has demonstrably improved the effectiveness of anticancer drugs., Thus, HK2 stands as a promising therapeutic target, though considering its ubiquitous expression and crucial role in energy metabolism, a reduction rather than complete inhibition of its activity should be pursued. Non-insulin-dependent diabetes mellitus A study on non-insulin-dependent diabetes mellitus (NIDDM) revealed low basal G6P levels in NIDDM patients that failed to increase with the addition of insulin. One possible cause is decreased phosphorylation of glucose due to a defect in HK2, which was confirmed in further experiments. However, the study could not establish any links between NIDDM and mutations in the HK2 gene, indicating that the defect may lie in HK2 regulation. Interactions HK2 is known to interact with: VDAC. Interactive pathway map See also Hexokinase HK1 HK3 Glucokinase References Further reading