G protein-dependent vectorial transportation of receptors, ion channels, and transporters

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G protein-coupled or tyrosine kinase-linked receptors are involved in the regulations of many signal transductions. After the stimulation of these membrane receptors, not only the receptor molecules themselves but also ion channels or transporters are internalized into the cells through endocytic pathways. Thus, there is vectorial transportation in the membrane trafficking. In this study, we investigated the molecular mechanisms whereby these receptors regulate the vectorial transportation.The major findings obtained in this study are summarized as follows.1) The lipid kinase phosphatidylinositol (PI) 3-OH kinase is synergistically stimulated by different types of membrane receptors, such as G protein-coupled and tyrosine kinase-linked receptors. We have found that the class I (p110beta subtype) PI 3-OH kinase is responsible for the synergistic stimulation and that its adaptor, Gab2, is involved in the signaling through its dual phosphorylation by Src tyrosine kinase and ERK. 2) The small GTPase Rab family are involved in membrane trafficking pathways. We have identified novel members of the RIN family as guanine nucleotide-exchange factors (GEFs) for Rab5. The RIN family, which contains many functional domains, such as SH2, Pro-rich region (binding to SH3), Vps9 (GEF), and RA (Ras-association), appear to act as adaptors or scaffold proteins in early steps of the endocytic pathway. 3) We have also identified novel family of Ras-like small GTPases, Di-Ras, Rheb, which might be involved in membrane trafficking pathways. Rheb expression in culture cells induced formation of the cytoplasmic large vacuoles, which are characterized as late endocytic (late endosome-and lysosome-like) components. Rheb appears to regulate the internalization of glutamate transporter in glial cells.