SLC2A4RG

Last update 08 May 2025

Basic Info

Synonyms

GEF, GLUT4 enhancer factor, HDBP-1

+ [6]

Introduction

Transcription factor involved in SLC2A4 and HD gene transactivation. Binds to the consensus sequence 5'-GCCGGCG-3'.

100 Clinical Results associated with SLC2A4RG

100 Translational Medicine associated with SLC2A4RG

0 Patents (Medical) associated with SLC2A4RG

927

Literatures (Medical) associated with SLC2A4RG

01 Apr 2025·Archives of Biochemistry and Biophysics

Ras activation by hydrostatic pressure involves GDP release and is enhanced by GAP and GEF in vitro

Article

Author: Ushida, Takashi ; Taninaka, Yuki ; Chang, Minki ; Furukawa, Katsuko ; Matsuda, Teruhiko ; Uyeda, Taro Q P

Hydrostatic pressure (HP) is a necessary stimulus for cell differentiation and growth in cultured chondrocytes. We hypothesized that Ras activation is involved in HP-induced cellular reactions and examined whether Ras, with or without its regulators, has HP sensitivity by using an in vitro system to measure Ras activity under HP. This in vitro system included mRaichu, a FRET-based Ras activity probe. We found that HP of 28 MPa activated Ras activity by 10.7 % in the absence of the GAP and GEF domains. HP also induced rapid dissociation of a fraction of mant-GDP from Ras. HP-induced dissociation of GDP from Ras in the presence of GTP would explain the HP-induced Ras activation. A low concentration of GAP domain derived from p120GAP enhanced the HP-induced Ras activation to 15.3 % by decreasing the Ras activity under atmospheric pressure (AP). In contrast, high concentrations of the GAP domain removed the HP activation by reducing the Ras activity to very low levels under both HP and AP conditions. Moreover, a broad concentration range (1-1000 nM) of GEF domain derived from hSOS-1 enhanced the HP-induced Ras activation. HP also increased Ras activity under conditions containing GEF and GAP domains to mimic cellular Ras activity. Based on these results, we propose that the HP-induced Ras activation revealed in this study is involved in the differentiation and growth stimulation of chondrocytes subjected to HP.

01 Apr 2025·Journal of Biological Chemistry

A p.N92K variant of the GTPase RAC3 disrupts cortical neuron migration and axon elongation

Article

Author: Nagata, Koh-Ichi ; Sugawara, Ryota ; Ueda, Hiroshi ; Ogata, Kazuhiro ; Ito, Hidenori ; Tabata, Hidenori ; Scala, Marcello ; Hamada, Keisuke

RAC3 encodes a small GTPase of the Rho family, crucial for actin cytoskeleton organization and signaling pathways. De novo deleterious variants in RAC3 cause neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (NEDBAF). Disease-causing variants thus far reported are thought to impact key conserved regions within RAC3, such as the P-loop, switch I/II, and G boxes, which are essential for the interaction with regulatory proteins and effectors. Recently, however, a novel variant, c.276T > A, p.N92K, was identified in a prenatal case with complex brain malformations. This variant, located outside the core functional regions, represents a unique class of RAC3 pathogenic mutations. We investigated the variant's effects using in vitro, in silico, and in vivo approaches. Overexpression of RAC3-N92K in primary hippocampal neurons impaired differentiation, leading to round cell shape with lamellipodia, suggesting that RAC3-N92K is active. Biochemical studies showed that RAC3-N92K is (1) resistant to GAP-mediated inactivation, (2) responsive to GEF activation, and (3) capable of interacting with RAC effectors PAK1 and MLK2, as well as Rho-kinase 1, activating gene expression through SRF, NFκB, and AP1 pathways. Structural analyses suggest that N92K disrupts GAP interactions but preserves interactions with GEF, PAK1, and MLK2. In vivo, RAC3-N92K expression in embryonic mouse cortical neurons led to migration defects and periventricular clustering during corticogenesis, along with impaired axon elongation. These findings indicate that RAC3-N92K's activated state significantly disrupts cortical development, expanding the genetic and pathophysiological spectrum of NEDBAF.

01 Apr 2025·Journal of Molecular Biology

Switch II pocket inhibitor allosterically freezes KRASG12Dnucleotide-binding site and arrests the GTPase cycle

Article

Author: Marshall, Christopher B ; Kim, Ha-Neul ; Ikura, Mitsuhiko ; Gebregiworgis, Teklab ; Uchida, Arisa ; Gasmi-Seabrook, Geneviève M C

KRAS is frequently mutated in multiple cancers, with the most common mutation being G12D. The recently developed KRAS^G12D inhibitor MRTX1133 binds a cryptic allosteric pocket near switch II (SII-P), similar to covalent G12C inhibitors, with remarkable picoM non-covalent affinity. Despite its advancement to clinical trials, some aspects of the molecular mechanisms-of-action remain unclear, indicating a need to uncover the mechanisms underlying MRTX1133 efficacy and potential acquired resistance, thus we characterized the biochemical and biophysical outcomes of MRTX1133 binding KRAS. Hydrogen/deuterium exchange experiments showed that MRTX1133 binding to the induced SII-P reduces the overall conformational plasticity of KRAS^G12D. This extends well beyond SII-P, with the nucleotide-binding regions (P-loop and G-3/4/5-box motifs) particularly exhibiting stabilization. This conformational rigidification by MRTX1133 is coupled with complete arrest of the GTPase cycle: When the compound engages KRAS^G12D-GDP, both intrinsic and GEF-mediated nucleotide exchange are blocked while engagement of KRAS^G12D-GTP blocks both intrinsic and GAP-mediated hydrolysis. MRTX1133 attenuates the interaction between activated KRAS^G12D and the RAS-binding domain of the effector BRAF. The binding site in Switch I remains flexible, which enables binding, albeit with ∼10-fold lower affinity, and remarkably, this interaction with BRAF reverses the compound's blockage of intrinsic GTP hydrolysis. Unlike KRAS^WT, GDP-loaded KRAS^G12D surprisingly maintains a low-affinity interaction with BRAF-RBD, but MRTX1133 can circumvent this mutant-specific abnormal interaction. Taken together, MRTX1133 allosterically 'freezes' the KRAS^G12D nucleotide-binding site conformation, arresting the canonical GTPase cycle of this oncogenic mutant. This provides a framework for understanding the mechanisms-of-action of SII-P-directed inhibitors and how tumours may acquire resistance.

Analysis

Perform a panoramic analysis of this field.

view full example data

AI Agents Built for Biopharma Breakthroughs

Accelerate discovery. Empower decisions. Transform outcomes.

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

SLC2A4RG

Basic Info

Related

Analysis