Rubicon, a subunit of the Beclin 1-PI3-kinase complex and its homologue, PLEKHM1, negatively regulate endocytic pathway through the interaction with Rab7. Synchronous association with the Beclin 1–PI3-kinase complex and Rab7 is necessary for the function of Rubicon, but not PLEKHM1.

The amyloid precursor protein (APP) is anterogradely transported by conventional kinesin in a distinct transport vesicle, but both the biochemical composition of such a vesicle and the specific kinesin-1 motor responsible for transport are poorly defined. APP may be sequentially cleaved by ␤-and ␥-secretases leading to accumulation of ␤-amyloid (A␤) peptides in brains of Alzheimer's disease patients, whereas cleavage of APP by ␣-secretases prevents A␤ generation. Here, we demonstrate by time-lapse analysis and immunoisolations that APP is a cargo of a vesicle containing the kinesin heavy chain isoform kinesin-1C, the small GTPase Rab3A, and a specific subset of presynaptic protein components. Moreover, we report that assembly of kinesin-1C and APP in this vesicle type requires Rab3A GTPase activity. Finally, we show cleavage of APP intransportvesiclesby␣-secretaseactivity,likelymediatedbyADAM10.Together,thesedataindicatethatmaturationofAPPtransportvesicles, including recruitment of conventional kinesin, requires Rab3 GTPase activity.

Rab3A small G protein is a member of the Rab family and is most abundant in the brain, where it is localized on synaptic vesicles. Evidence is accumulating that Rab3A plays a key role in neurotransmitter release and synaptic plasticity. Rab3A cycles between the GDP-bound inactive and GTP-bound active forms, and this change in activity is associated with the trafficking cycle of synaptic vesicles at nerve terminals. Rab3 GTPase-activating protein (GAP) stimulates the GTPase activity of Rab3A and is expected to determine the timing of the dissociation of Rab3A from synaptic vesicles, which may be coupled with synaptic vesicle exocytosis. Rab3 GAP consists of two subunits: the catalytic subunit p130 and the noncatalytic subunit p150. Recently, mutations in p130 were found to cause Warburg Micro syndrome with severe mental retardation. Here, we generated p130-deficient mice and found that the GTPbound form of Rab3A accumulated in the brain. Loss of p130 in mice resulted in inhibition of Ca 2؉ -dependent glutamate release from cerebrocortical synaptosomes and altered short-term plasticity in the hippocampal CA1 region. Thus, Rab3 GAP regulates synaptic transmission and plasticity by limiting the amount of the GTP-bound form of Rab3A.Rab3A ͉ Rab3 GAP p130 ͉ neurotransmitter release ͉ synaptic plasticity ͉ Warburg Micro syndrome

Neurite outgrowth is the first step in the processes of neuronal differentiation and regeneration and leads to synaptic polarization and plasticity. Rab13 small G protein shows an increased mRNA expression level during neuronal regeneration; it is therefore thought to be involved in this process. We previously identified JRAB ( Neuronal cells are symmetrically shaped in the very early stages of development. When fully developed, they are asymmetrical, with one long thin axon. The polarization of cell morphology and the creation of synaptic contacts via elongation of the axon and dendrites during development is a crucial event in the process of neuronal differentiation and regeneration and is called neurite outgrowth (18,23). During neurite outgrowth, neuronal cells are stimulated to extend processes by a multitude of extracellular signals and eventually establish synaptic contacts by which they are able to communicate with one another.

Background: The Rab13-JRAB system transports cell adhesion molecules. Results: JRAB interacts with actinins and F-actin and spatiotemporally regulates actin dynamics via a conformational change that is dependent upon Rab13. Conclusion: Rab13 and JRAB regulate reorganization of the actin cytoskeleton throughout epithelial junctional development from establishment to maturation of cell-cell adhesion. Significance: The Rab13-JRAB system may simultaneously coordinate vesicle transport and actin cytoskeletal organization.