MMP-9 Signaling Pathways That Engage Rho GTPases in Brain Plasticity

Abstract

The extracellular matrix (ECM) has been identified as a critical factor affecting synaptic function. It forms a functional scaffold that provides both the structural support and the reservoir of signaling molecules necessary for communication between cellular constituents of the central nervous system (CNS). Among numerous ECM components and modifiers that play a role in the physiological and pathological synaptic plasticity, matrix metalloproteinase 9 (MMP-9) has recently emerged as a key molecule. MMP-9 may contribute to the dynamic remodeling of structural and functional plasticity by cleaving ECM components and cell adhesion molecules. Notably, MMP-9 signaling was shown to be indispensable for long-term memory formation that requires synaptic remodeling. The core regulators of the dynamic reorganization of the actin cytoskeleton and cell adhesion are the Rho family of GTPases. These proteins have been implicated in the control of a wide range of cellular processes occurring in brain physiology and pathology. Here, we discuss the contribution of Rho GTPases to MMP-9-dependent signaling pathways in the brain. We also describe how the regulation of Rho GTPases by post-translational modifications (PTMs) can influence these processes.

Keywords: MMP-9; extracellular matrix; post-translational modifications; small Rho GTPases; synaptic plasticity.

Figure 1

MMP-9 proteolytic activity causes Cdc42 and Rac1 activation in cultured cortical neurons. Cells were treated with autoactivaiting matrix metalloproteinase 9 (aaMMP-9) for 5 and 10 min and the activity of Rho-GTPases was analyzed using a pull-down assay. Western blots show levels of the activated form (coupled with GTP) and total levels of Cdc42 and Rac1. GTPγS served as a positive control for pull-down assay.

Figure 2

The potential relationship between MMP-9-driven substrates shedding and Rho GTPases signaling in brain plasticity.