Functions and modes of action of small G proteins in cell adhesion and migration

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When epithelial cells start to migrate, cell-cell junctions are first disrupted. During migration, membrane protrusions, such as lamellipodia and filopodia, at the cell front, and retraction at the cell rear are externally observed, and dynamic reorganization of the actin cytoskeleton is internally observed. We have recently clarified that the Rho and Rab family small G proteins coordinately regulate cell adhesion and migration of cultured MDCK cells. The Rab family consists of over thirty members. We have found that some Rab family members are involved in HGF- or phorbol esterinduced endocytosis and recycling of cadherin and integrin. Rab11, a member of Rab family, has been implicated in vesicle recycling. During this support from 1999 to 2000, we have focused on studying the function and mode of action of Rab11 in cell migration. The results obtained are as follows :(1) We have isolated a downstream target of Rab11, named Rabphilin-11, from bovine brain. We have found that rabphilin-11 is localized at perinuclear regions, presumably the Golgi complex and recycling endosomes in MDCK cells.(2) We have found that Rabphilin-11 is localized not only at perinuclear regions but also along microtubules, which are oriented toward membrane lammelipodia in HeLa cells cultured on fibronectin. Overexpression of rabphilin-11 mutant reduces accumulation of transferrin at perinuclear regoins and cell migratoin.(3) We have found that rabphilin-11 directly binds the mammalian counterpart of yeast Sec13 proteins (mSec13) in cell-free and intact cell systems. Disruption of the rabphilin-11-mSec13 interaction by overexpression of the mSec13-binding region of rabphilin-11 impairs vesicle trafficking.