GDI2

Last update 08 May 2025

Basic Info

Synonyms

GDI-2, GDI2, GDP dissociation inhibitor 2

+ [4]

Introduction

GDP-dissociation inhibitor preventing the GDP to GTP exchange of most Rab proteins. By keeping these small GTPases in their inactive GDP-bound form regulates intracellular membrane trafficking (PubMed:25860027). Negatively regulates protein transport to the cilium and ciliogenesis through the inhibition of RAB8A (PubMed:25860027).

100 Clinical Results associated with GDI2

100 Translational Medicine associated with GDI2

0 Patents (Medical) associated with GDI2

Literatures (Medical) associated with GDI2

01 Aug 2025·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

The phosphomimetic Rab10 T73D mutation in mice leads to postnatal lethality and aberrations in neuronal development

Article

Author: Su, Bo ; Yu, Hui ; Zhang, Jing ; Han, DaoBin ; Zheng, Yuan ; Wang, LuWen

The phosphorylation of the evolutionarily conserved Thr73 residue of Rab10 has been implicated in various neurodegenerative diseases. However, its impact on neuronal physiological function remains poorly understood. In this study, we generated a novel mouse model constitutively expressing the phosphomimetic Rab10 T73D to investigate its effects. Our findings revealed that homozygous Rab10 T73D mutant mice were postnatally lethal and exhibited brain developmental defects characterized by cortical thinning and shortened neuronal processes. Further investigation demonstrated that cultured hippocampal neurons with homozygous T73D mutation displayed decreased axon development, with reduced accumulation of Rab10 at the tips of neuronal processes and increased Rab10 localization at lysosomes. Mechanistically, the T73D mutation induces a constitutively GTP-bound state and while substantially weakening interaction with GDI1, GDI2 and JIP1. These molecular alterations collectively lead to altered T73D Rab10-positive vesicle trafficking dynamics, manifesting as decreased anterograde transport and increased movement velocity. Notably, comparative localization studies in RPE cells confirmed fundamental discrepancies between T73D distribution patterns and authentic phosphorylated Rab10 dynamics, validating limitations of this phosphomimetic approach. Collectively, our study elucidates the potential physiological roles of phosphorylated Rab10 in the regulation of neuronal process outgrowth and underscores its significance in the neural system. Additionally, it highlights the limitations of the T73D mutant in fully mimicking Rab10 phosphorylation.

06 Dec 2024·Science Advances

A trafficking regulatory subnetwork governs α _V β ₆ integrin-HER2 cross-talk to control breast cancer invasion and drug resistance

Article

Author: Marshall, John F. ; Rigby, Megan E. ; Marotta, Valeria E. ; Maldonado, Horacio ; Rusilowicz-Jones, Emma V. ; Dreger, Marcel ; Kyriakou, Theano ; Wang, Jun ; Bedgood, Lara D. ; Macpherson, Iain R. ; Webster, Justine M. ; Coulson, Judy M. ; Hurlstone, Adam ; Wolanska, Katarzyna I. ; Morgan, Mark R.

HER2 and α V β 6 integrin are independent predictors of breast cancer survival and metastasis. We identify an α V β 6 /HER2 cross-talk mechanism driving invasion, which is dysregulated in drug-resistant HER2+ breast cancer cells. Proteomic analyses reveal ligand-bound α V β 6 recruits HER2 and a trafficking subnetwork, comprising guanosine triphosphatases RAB5 and RAB7A and the Rab regulator guanine nucleotide dissociation inhibitor 2 (GDI2). The RAB5/RAB7A/GDI2 functional module mediates direct cross-talk between α V β 6 and HER2, affecting receptor trafficking and signaling. Acute exposure to trastuzumab increases recruitment of the subnetwork to α V β 6 , but trastuzumab resistance decouples GDI2 recruitment. GDI2, RAB5, and RAB7A cooperate to regulate migration and transforming growth factor–β activation to promote invasion. However, these mechanisms are dysregulated in trastuzumab-resistant cells. In patients, RAB5A , RAB7A , and GDI2 expression correlates with patient survival and α V β 6 expression predicts relapse following trastuzumab treatment. Thus, the RAB5/RAB7A/GDI2 subnetwork regulates α V β 6 -HER2 cross-talk to drive breast cancer invasion but is subverted in trastuzumab-resistant cells to drive α V β 6 -independent and HER2-independent tumor progression.

01 Apr 2024·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

GDI2 deletion alleviates neurodegeneration and memory loss in the 5xFAD mice model of Alzheimer's disease

Article

Author: He, Xiuqing ; You, Pan ; Wang, Luwen ; Su, Bo ; Yu, Hui ; Li, Jie ; Han, Daobin ; Wang, Meitian

Accumulation of insoluble deposits of amyloid β-peptide (Aβ), derived from amyloid precursor protein (APP) processing, represents one of the major pathological hallmarks of Alzheimer's disease (AD). Perturbations in APP transport and hydrolysis could lead to increased Aβ production. However, the precise mechanisms underlying APP transport remain elusive. The GDP dissociation inhibitor2 (GDI2), a crucial regulator of Rab GTPase activity and intracellular vesicle and membrane trafficking, was investigated for its impact on AD pathogenesis through neuron-specific knockout of GDI2 in 5xFAD mice. Notably, deficiency of GDI2 significantly ameliorated cognitive impairment, prevented neuronal loss in the subiculum and cortical layer V, reduced senile plaques as well as astrocyte activation in 5xFAD mice. Conversely, increased activated microglia and phagocytosis were observed in GDI2 ko mice. Further investigation revealed that GDI2 knockout led to more APP co-localized with the ER rather than the Golgi apparatus and endosomes in SH-SY5Y cells, resulting in decreased Aβ production. Collectively, these findings suggest that GDI2 may regulate Aβ production by modulating APP intracellular transport and localization dynamics. In summary, our study identifies GDI2 as a pivotal regulator governing APP transport and process implicated in AD pathology; thus highlighting its potential as an attractive pharmacological target for future drug development against AD.

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GDI2

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