Vapb, short for Vesicle-associated membrane protein-associated protein B, is an ER-anchored protein that plays a crucial role in mediating tethers between the endoplasmic reticulum (ER) and membranes of other organelles, such as mitochondria. It is part of the VAPB-PTPIP51 complex which is involved in the formation and stability of mitochondria-associated endoplasmic reticulum membranes (MAMs), a key intracellular signaling hub regulating calcium homeostasis, lipid metabolism, mitochondrial function, and apoptosis [1,3]. It also interacts with IRS-1 to regulate insulin/IGF signaling by stabilizing IRS-1 through ER-targeting [2].

In animal models, knockout of VapB in mice led to down-regulation of IRS-1, suppression of insulin signaling, and glucose intolerance, indicating its importance in insulin/IGF signaling [2]. In a mouse middle cerebral artery occlusion (MCAO) model simulating cerebral ischemia-reperfusion injury, decreased VAPB-PTPIP51 expression was observed, and knockdown of VAPB exacerbated MAMs damage, excessive autophagy activation, and increased reactive oxygen species production, resulting in an enlarged infarct area and exacerbated neurological deficits [3]. In medulloblastoma cells, knockout of VAPB (VAPBKO) delayed cell cycle progression and decreased transcript levels of WNT-related proteins, suggesting its role in the proliferation of these cancer cells [4].

In conclusion, Vapb is essential for maintaining MAMs structure and function, regulating insulin/IGF signaling, and influencing cell proliferation in certain cancers. The use of gene knockout mouse models has provided valuable insights into its role in diseases such as insulin-related metabolic disorders, ischemic stroke, and medulloblastoma, highlighting its potential as a therapeutic target for these conditions.