Extracellular deposition of β-amyloid (Aβ) and intracellular hyperphosphorylated tau are the predominant pathological changes in Alzheimer's disease (AD). Increasing evidence demonstrates a critical role of a variety of small GTPases, namely Ras-related proteins (Rabs), in the pathogenesis of AD. As crucial regulators of intracellular membrane trafficking, alteration in Rab protein expression and function represents one of the primary factors contributing to the abnormal membrane trafficking in AD. Additionally, the Rab GTPases are also involved in the development of Aβ, tau and other pathological changes associated with AD. In this article, we conduct a comprehensive review on the primary functions of multiple Rab proteins and their involvement in the pathogenesis of AD.
Humans ; Alzheimer Disease ; rab GTP-Binding Proteins/metabolism* ; Amyloid beta-Peptides/metabolism* ; tau Proteins/metabolism*

Child ; Female ; Humans ; Hyperkinesis ; genetics ; Intellectual Disability ; genetics ; Mutation ; rab GTP-Binding Proteins ; genetics

As a member of the Ras superfamily, Rab proteins are small GTP-binding proteins. In the process of endocytosis of macromolecules and substances delivery between organelles, Rab proteins act on vesicle formation, transport, tethering and fusion by recruiting their effectors, therefore being key regulatory factors in vesicle trafficking. Disturbance of localizations and functions of Rab proteins and their effectors are involved in the pathogenesis of several diseases. This review focuses on the main functions of Rab proteins and their possible roles in the onset and progression of neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, and Huntington's disease.
Cell Movement ; Endocytosis ; Humans ; Neurodegenerative Diseases ; Protein Transport ; rab GTP-Binding Proteins/metabolism*

OBJECTIVE: To investigate the effect of inhibition of RAB27 protein family, which plays a pivotal role in exosome secretion, on biological behaviors of triple-negative breast cancer cells. METHODS: Quantitative real-time PCR and Western blotting were used to examine the expressions of RAB27 family and exosome secretion in 3 triple-negative breast cancer cell lines (MDA-MB-231, MDA-MB-468, and Hs578T) and a normal breast epithelial cell line (MCF10A). The effect of small interfering RNA (siRNA)-mediated silencing of RAB27a and RAB27b on exosome secretion in the 3 breast cancer cell lines was detected using Western blotting, and the changes in cell proliferation, invasion and adhesion were evaluated. RESULTS: Compared with normal breast epithelial cells, the 3 triple-negative breast cancer cell lines exhibited more active exosome secretion (P < 0.001) and showed significantly higher expressions of RAB27a and RAB27b at both the mRNA and protein levels (P < 0.01). Silencing of RAB27a in the breast cancer cells significantly down-regulated exosome secretion (P < 0.001), while silencing of RAB27b did not significantly affect exosome secretion. The 3 breast cancer cell lines with RAB27a silencing-induced down-regulation of exosome secretion showed obvious inhibition of proliferation, invasion and adhesion (P < 0.01) as compared with the cell lines with RAB27b silencing. CONCLUSION RAB27a plays central role in the exosome secretion in triple-negative breast cancer cells, and inhibiting RAB27a can inhibit the proliferation, invasion and adhesion of the cells.
Humans ; rab GTP-Binding Proteins/metabolism* ; Triple Negative Breast Neoplasms ; Cell Line, Tumor ; rab27 GTP-Binding Proteins/metabolism* ; RNA, Small Interfering/genetics* ; Cell Proliferation/genetics* ; Gene Expression Regulation, Neoplastic

Gene expression in rice roots under nutritional stress was studied using micro array techniques. The results showed that when re-supplied with sufficient amounts of nutrition after nutrition stress, the expression of OsPra2 (a small G protein which is homologous with Pea Pra2 protein) decreased in the plants root tissue. The cDNA sequence of the OsPra2 gene and its promoter, which is about 1 kb upstream of the translation origin point, was obtained using RT-PCR and PCR approaches. The OsPra2 protein contains four conserved GTP/GDP binding domains and specific domain of Rab small G protein family. The expression of OsPra2 and GST fusion protein in onion epidermal cells showed that OsPra2 protein was localized in the membrane and nucleus of the cell. The fusion expression of OsPra2 promoter and GUS reporter gene in transgenic rice suggested that the OsPra2 promoter allowed GUS expression in coleoptiles and roots. Compared with wild type rice, OsPra2 over expressed transgenic rice showed an obvious dwarf phenotype which resembles the BR deficient rice.
Amino Acid Sequence ; Base Sequence ; Cloning, Molecular ; Gene Expression Regulation, Plant ; Genes, Plant ; Molecular Sequence Data ; Oryza ; genetics ; metabolism ; Plant Proteins ; genetics ; metabolism ; Plants, Genetically Modified ; genetics ; metabolism ; Sequence Homology, Amino Acid ; rab GTP-Binding Proteins ; genetics ; metabolism

Animals ; Cell Nucleus Size ; genetics ; Cell Proliferation ; genetics ; Embryo Loss ; genetics ; pathology ; Embryo, Mammalian ; metabolism ; pathology ; Embryonic Stem Cells ; cytology ; Endoplasmic Reticulum ; genetics ; Homologous Recombination ; Mice ; rab GTP-Binding Proteins ; deficiency ; genetics ; metabolism

NESCA, a newly discovered signaling adapter protein in the NGF-pathway, contains a RUN domain at its N-terminus. Here we report the crystal structure of the NESCA RUN domain determined at 2.0-Å resolution. The overall fold of the NESCA RUN domain comprises nine helices, resembling the RUN domain of RPIPx and the RUN1 domain of Rab6IP1. However, compared to the other RUN domains, the RUN domain of NESCA has significantly different surface electrostatic distributions at the putative GTPase-interacting interface. We demonstrate that the RUN domain of NESCA can bind H-Ras, a downstream signaling molecule of TrkA, with high affinity. Moreover, NESCA RUN can directly interact with TrkA. These results provide new insights into how NESCA participates in the NGF-TrkA signaling pathway.
Adaptor Proteins, Signal Transducing ; chemistry ; genetics ; metabolism ; Amino Acid Sequence ; Binding Sites ; Crystallography, X-Ray ; Gene Expression ; Humans ; Models, Molecular ; Molecular Sequence Data ; Nerve Growth Factor ; chemistry ; genetics ; metabolism ; Oncogene Protein p21(ras) ; chemistry ; genetics ; metabolism ; Protein Binding ; Protein Structure, Tertiary ; Receptor, trkA ; chemistry ; genetics ; metabolism ; Recombinant Proteins ; chemistry ; genetics ; metabolism ; Sequence Homology, Amino Acid ; Signal Transduction ; rab GTP-Binding Proteins ; chemistry

Akt (protein kinase B (PKB)) is a serine/threonine kinase that acts in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. The PI3K/Akt signaling pathway, triggered by growth factors and hormones including vasopressin, is an important pathway that is widely involved in cellular mechanisms regulating transcription, translation, cell growth and death, cell proliferation, migration, and cell cycles. In particular, Akt and Akt substrate protein of 160 kDa (AS160) are likely to participate in the trafficking of aquaporin-2 (AQP2) in the kidney collecting duct. In this study, we demonstrated that 1) small interfering RNA (siRNA)-mediated gene silencing of Akt1 significantly decreased Akt1 and phospho-AS160 protein expression; and 2) confocal laser scanning microscopy of AQP2 in mouse cortical collecting duct cells (M-1 cells) revealed AS160 knockdown by siRNA increased AQP2 expression in the plasma membrane compared with controls, despite the absence of dDAVP stimulation. Thus, the results suggest that PI3K/Akt pathways could play a role in AQP2 trafficking via the AS160 protein.
Animals ; Aquaporin 2 ; Cell Cycle ; Cell Death ; Cell Membrane ; Deamino Arginine Vasopressin ; Gene Silencing ; Intercellular Signaling Peptides and Proteins ; Kidney Tubules, Collecting ; Membranes ; Mice ; Microscopy, Confocal ; Phosphatidylinositol 3-Kinase ; Phosphotransferases ; Protein Transport ; Proto-Oncogene Proteins c-akt ; rab GTP-Binding Proteins ; RNA, Small Interfering ; Vasopressins ; Water

AIMTo show whether molecular motor dynein on a microtubule track, molecular motor myosin Va, motor recruiter myosin Va, VIIa-Rab27a/b interacting protein (MyRIP), and vesicle receptor Rab27b on an F-actin track were present during human and monkey spermiogenesis involving intramanchette transport (IMT).

METHODSSpermiogenic cells were obtained from three men with obstructive azoospermia and normal adult cynomolgus monkey (Macaca fascicularis). Immunocytochemical detection and reverse transcription-polymerase chain reaction (RT-PCR) analysis of the proteins were carried out. Samples were analyzed by light microscope.

RESULTSUsing RT-PCR, we found that dynein, myosin Va, MyRIP and Rab27b were expressed in monkey testis. These proteins were localized to the manchette, as shown by immunofluorescence, particularly during human and monkey spermiogenesis.

CONCLUSIONWe speculate that during primate spermiogenesis, those proteins that compose microtubule-based and actin-based vesicle transport systems are actually present in the manchette and might possibly be involved in intramanchette transport.

Actins ; metabolism ; Adult ; Animals ; Biological Transport ; physiology ; Dyneins ; metabolism ; Humans ; Macaca fascicularis ; Male ; Microtubules ; metabolism ; Myosin Heavy Chains ; metabolism ; Myosin Type V ; metabolism ; Myosins ; metabolism ; Spermatids ; cytology ; metabolism ; Spermatogenesis ; physiology ; Testis ; cytology ; metabolism ; Transport Vesicles ; physiology ; Vesicular Transport Proteins ; metabolism ; rab GTP-Binding Proteins ; metabolism

Low molecular weight GTP-binding proteins are molecular switches that are believed to play pivotal roles in cell growth, differentiation, cytoskeletal organization, and vesicular trafficking. Rab proteins are key players in the regulation of vesicular transport, while Rho family members control actin-dependent cell functions, i.e. the regulation of cytoskeletal organization in response to extracelluar growth factors and in dendritic neuron development. In this study, we have examined the regulation of small GTP-binding proteins that are implicated in neurosecretion and differentiation of neuron during ageing processes. Comparison of small GTP-binding proteins from the synaptosome and crude synaptic vesicles (LP2 membranes) of 2 months and 20 months old rat brain respectively showed no difference in the level of Rab family proteins (Rab3A and Rab5A). However, Rho family proteins such as RhoA and Cdc42 were elevated in LP2 membranes of the aged brain. The dissociation of Rab3A by Ca2+/calmodulin (CaM) from SV membranes was not changed during aging. Ca2+/CaM stimulated phosphorylation of the 22 and 55-kDa proteins in SV membranes from the aged rat brain, and inhibited phosporylation of 30-kDa proteins. GTPgammaS inhibited phosphorylation of the 100-kDa proteins and stimulated phosphorylation of the 70 kDa in LP2 membranes from both the young and aged rat brains, whereas GDPbetaS caused just the opposite reaction. These results suggest that protein phosphorylation and regulation of Rho family GTPases in rat brain appears to be altered during ageing processes.
*Aging ; Animal ; Brain/metabolism ; Calcium/pharmacology ; Cattle ; Comparative Study ; GTP-Binding Proteins/*metabolism ; Guanosine 5'-O-(3-Thiotriphosphate)/metabolism ; Molecular Weight ; Phosphorylation/drug effects ; Rats ; Rats, Sprague-Dawley ; Synaptic Membranes/*metabolism ; Synaptosomes/*metabolism ; cdc42 GTP-Binding Protein/biosynthesis/metabolism ; rab3A GTP-Binding Protein/metabolism ; rab5 GTP-Binding Proteins/metabolism ; rhoA GTP-Binding Protein/biosynthesis/metabolism