![]() Upon its activation, Rab35 presumably recruits molecular effectors to membranes. The DENN domain of connecdenn binds Rab35 and functions as a GEF for this GTPase ( 8). showed that Rab35 is activated by connecdenn ( 8), a component of clathrin-coated vesicles that can bind to lipids or membranes through its Differentially Expressed in Neoplastic versus Normal cells (DENN) domain. Recently, it was demonstrated that Rab35 and its novel GAP, Skywalker, regulate endosomal trafficking of synaptic vesicles at Drosophila neuromuscular junctions ( 14).Īllaire et al. In addition, Rab35 is linked to actin dynamics during neurite outgrowth and to actin bundling during bristle formation in D. Rab35, which is localized both to endosomes and the plasma membrane ( 10), is also required for endosomal secretion during immunological synapse formation and stabilization and successful abscission of the cytokinesis bridge ( 10, 11). ![]() Moreover, Rab35 is required for recycling of KCa2.3 Ca 2+-activated K + channels ( 9). One Rab that has recently been an intense focus of study is Rab35, a member of the Rab protein family that regulates fast recycling of receptors such as major histocompatibility class I (MHC I) ( 8). Particularly well studied are Rab5, which regulates trafficking of newly internalized receptors to EE, and Rab4, which is involved in both the fast and slow recycling pathways of the transferrin receptor (( 4- 7)).Īlthough many Rab proteins and the molecular mechanisms by which they control different trafficking pathways have been very well characterized, others are not as well understood. Hydrolysis activity by a family of proteins known as Rab GTPase activating proteins (GAPs) facilitates conversion of Rab-GTP to Rab-GDP, and the Rab is generally released from membranes to the cytoplasm (reviewed in ( 3)). Upon binding to GTP, Rab proteins recruit their molecular effectors, which are proteins that interact specifically with GTP-bound Rabs and carry out select effector functions. The guanine nucleotide exchange factors (GEFs) of Rab proteins catalyze the exchange of GDP with GTP. The Rab-GTP-binding proteins are molecular switches that can either bind GTP when in an activated state and associate with membranes, or they are inactive, GDP-bound, and mostly localized to the cytoplasm (reviewed in ( 3)). Many proteins regulate these trafficking pathways, with the Ras-like small GTP-binding proteins (Rab-GTP-binding proteins) playing a central role. While some receptors are sorted for lysosomal degradation, other receptors are recycled back to the plasma membrane, either in a direct pathway from EE (fast recycling) or indirectly through the endocytic recycling compartment (ERC) (reviewed in ( 1, 2)). Upon endocytosis, newly internalized vesicles are directed to early endosomes (EE). Overall, our data suggest a model in which Rab35 is a critical upstream regulator of MICAL-L1 and Arf6, while both MICAL-L1 and Arf6 regulate Rab8a function.Įndocytosis is a highly conserved process across species in which nutrients, and lipids are internalized into the cells. Moreover, we demonstrate that Arf6 forms a complex with MICAL-L1 and plays a role in its recruitment to tubular endosomes. ![]() Over-expression of active Rab35 impairs the recruitment of MICAL-L1 to tubular recycling endosomes, whereas Rab35 depletion promotes enhanced MICAL-L1 localization to these structures. First, we demonstrate that Rab35 is a MICAL-L1 binding partner in vivo. In this study, we identify two GTP-binding proteins as interaction partners of the endocytic regulatory protein MICAL-L1. Despite our familiarity with many of the key regulatory proteins involved in this process, our understanding of the mode by which these proteins cooperate and the sequential manner in which they function remains limited. A variety of small GTP-binding proteins regulate receptor recycling. Once internalized, receptors can either be degraded or recycled back to the plasma membrane. Endocytosis is a conserved process across species in which cell surface receptors and lipids are internalized from the plasma membrane.
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