Abstract
Small GTPases participate in a broad range of cellular processes such as proliferation, differentiation, and migration. The exchange of GDP for GTP resulting in the activation of these GTPases is catalyzed by a group of enzymes called guanine nucleotide exchange factors (GEFs), of which two classes: Dbl-related exchange factors and the more recently described dedicator of cytokinesis proteins family exchange factors. Increasingly, deregulation of normal GEF activity or function has been associated with a broad range of disease states, including neurodegeneration and neurodevelopmental disorders. In this review, we examine this evidence with special emphasis on the novel role of Rho guanine nucleotide exchange factor (RGNEF/p190RhoGEF) in the pathogenesis of amyotrophic lateral sclerosis. RGNEF is the first neurodegeneration-linked GEF that regulates not only RhoA GTPase activation but also functions as an RNA binding protein that directly acts with low molecular weight neurofilament mRNA 3′ untranslated region to regulate its stability. This dual role for RGNEF, coupled with the increasing understanding of the key role for GEFs in modulating the GTPase function in cell survival suggests a prominent role for GEFs in mediating a critical balance between cytotoxicity and neuroprotection which, when disturbed, contributes to neuronal loss.
Highlights
Small GTPases are low-molecular-weight guanine nucleotide-binding proteins that function as binary molecular switches by alternating between an active GTP-bound state and an inactive GDP-bound state and in doing so, regulate the activation of several effectors (Figure 1)
Most guanine nucleotide exchange factors (GEFs) belong to two broad families: the classical diffuse B-cell lymphoma (Dbl)homology family in which the catalytic function is exerted by a tandem of two domains [a Dbl-homology domain (DH) and an adjacent pleckstrin-homology domain (PH) that together bind other proteins and phospholipids; Snyder et al, 2002; Rossman et al, 2005; Miller et al, 2014]; and, the dedicator of cytokinesis proteins (Dock) family of atypical GEFs that lack the Dbl domain
The associated diseases range from lethal childhood onset disorders such a vanishing white matter (VWM) disease, to developmental disorders such as the autism spectrum disorders, through to the fatal adult onset disorder amyotrophic lateral sclerosis (ALS)
Summary
Small GTPases are low-molecular-weight (approximately 21 kDa) guanine nucleotide-binding proteins that function as binary molecular switches by alternating between an active GTP-bound state and an inactive GDP-bound state and in doing so, regulate the activation of several effectors (Figure 1). The activation of small GTPases such as Rho or Rab proteins requires the participation of specialized enzymes called guanine nucleotide exchange factors (GEFs) which catalyze the exchange of GTP for GDP in the GTPase with the requirement of Mg2+. This event generates a GTP-bound active GTPase. The highly conserved DH domain of the Dbl family of GEFs targets Dbl GEFs to the plasma membrane where binding to phospholipids is driven by the PH domain, while the DH domain interacts with inactive GTPase-GDP and catalyzes the exchange of GDP for GTP, activating the GTPase. Dbl GEFs are a highly complex family of about 80 proteins containing a variety of differing functional domains, including: (1) domains that modulate protein–protein interactions such as Proline rich domains (Ahn and Ye, 2005), PDZ binding domains (Garcia-Mata and Burridge, 2007), SH3 domains (van Rijssel and van Buul, 2012) and Fibronectin type-III domains (Rabiner et al, 2005); (2) modulators of GEF activity such as APC-binding region domains (Zhang et al, 2012) and Calponin homology domains (part of the actin binding domain superfamily; Yu et al, 2010); (3) modulators of plasma membrane interactions and localization such as FAK recognition
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