The Voltage-dependent Anion Channel (VDAC) Binds Tissue-type Plasminogen Activator and Promotes Activation of Plasminogen on the Cell Surface

Abstract

Background:The VDAC receptor, a major mitochondrial protein, is also present in the plasma membrane of normal brain cells. Results: VDAC binds t-PA and stimulates plasminogen activation in normal and injured brain cells. Conclusion: Formation of the ternary VDAC⅐t-PA⅐plasminogen complex enhances both t-PA activity and plasminogen activation.Significance: This ternary complex may play a significant role in normal and injured brain physiology.

Binding of Tissue-type Plasminogen Activator to the Glucose-regulated Protein 78 (GRP78) Modulates Plasminogen Activation and Promotes Human Neuroblastoma Cell Proliferation in Vitro

“…Both Pg and t-PA are central to mechanisms that control multiple forms of synaptic plasticity and memory (42,43). In a previous study, we proposed a model in which VDAC potentiates t-PA-mediated plasmin formation (7). With the results of this study, we can expand this model to include the association of VDAC with GRP78.…”

“…As previously observed, Pg K5 may inhibit cell growth; however, its role is short-lived because it may be inactivated after reduction by the NADH-dependent activity of VDAC (7), although binding of the microplasminogen/microplasmin domain to the Lys 633 -Asp 647 GRP78 COOH-terminal domain may induce a further increase of cell proliferation. Because t-PA in the brain is the most abundant serine protease (44) and because the brain is an organ usually devoid of fibrinogen, GRP78 and VDAC mimic fibrin to enhance the activation of locally synthesized Pg, which can then act on non-fibrin substrates (45), such as VDAC itself, which not only mimics fibrin, but also serves as a Pm substrate (7). Therefore, this fibrin-independent mechanism may shift the conformational equilibrium of the protease domain of t-PA to the fully active form, and may also be necessary to promote brain cell proliferation and survival.…”

“…Both Pg fragments induce Ca 2ϩ signaling cascades; however, K5 acts through VDAC and microplasminogen acts via GRP78 (5). Cell surface VDAC is also a receptor for tissue-type plasminogen activator (t-PA), and as a result of this interaction, t-PA activity and Pg activation are enhanced (7).…”

Tissue plasminogen activator regulates Purkinje neuron development and survival

“…Statistical analyses further suggest that (i) changes in the integrity of the cell plasma membrane, where VDAC1 also is located (Fig. 5C) (35), may contribute to PN degeneration (Fig. 7I); (ii) VDAC-associated mitochondrial ΔΨm correlated positively and mitochondrial diameter correlated negatively with PN viability (Fig.…”

“…5 A and B). Because VDAC in both the mitochondrial outer membrane and the cellular plasma membrane (35) (Fig. 5C) is a gatekeeper regulating cell life and death (32,36), we explored whether VDAC affects nr PN degeneration.…”