Biology Reference
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cell-cell adhesion by promoting the internalization of E-cadherin, the main
adhesive component of adherens junctions (Palacios et al., 2001). All together,
these findings are suggestive of cell-type-specific mechanisms associated with
ARF6 function in the endocytic pathway.
Evidence is accumulating that uptake and insertion of membrane at the
plasma membrane is important for cellular processes such as cell motility and
phagocytosis (reviewed in Bretscher and Aguado-Velasco, 1998; Mellman,
2000). The observations that inhibition of ARF6 activity interferes with cell
spreading, cell motility, and phagocytosis (Zhang et al., 1998; Song et al.,
1998; Santy and Casanova, 2001; Palacios et al., 2001) also support the
importance of the recycling pathway for processes requiring membrane
protrusion activities. Phagocytosis is triggered by the recognition of ligands
exposed on the particle surface by specific receptors on the phagocytic cell
(Aderem and Underhill, 1999). Receptor clustering activates a signalling
cascade, which in the case of FcgRs involves tyrosine kinases and PI3K (Cox
and Greenberg, 2001), leading to the formation of actin-rich pseudopods that
progressively engulf the particle in a zipper-like mechanism. It is generally
accepted that actin polymerization provides the force necessary for pseudopod
extension, and in support of this, Rho-family members are known to be
essential for phagocytosis (Castellano et al., 2001). In addition, exocytosis of
membrane from internal compartments contributes to pseudopod formation
(Booth et al., 2001). In particular, endocytic vesicles bearing VAMP3 (vesicle-
associated membrane protein 3) are delivered to the site of phagocytosis
suggesting that recycling from endocytic compartments contributes to
pseudopod formation (Bajno et al., 2000). ARF6 activity was known to be
required during FcgR-mediated phagocytosis (Zhang et al., 1998), however
the precise function of ARF6 in phagocytosis remains largely unknown.
Recently we began to investigate the role of ARF6 during phagocytosis in
macrophages. Our data suggest that local activation of ARF6 at the plasma
membrane following FcgR-clustering controls the polarized delivery of
membrane components that trac through the recycling pathway and are
essential for pseudopod formation (Niedergang et al., submitted).
Events downstream of ARF6 activation
The identification of the downstream mechanisms by which ARF6:GTP
controls membrane tra
cking in the endocytic pathway remains a major
issue. Two well-characterized ARF effectors are phospholipase D (PLD) and
phosphatidylinositol (4)-phosphate 5-kinase (PIP 5K) (Cockcroft, 2001;
Honda et al., 1999). PLDs convert phosphatidylcholine into phosphatidic
acid (PA), while PIP 5-kinase catalyses the production of phosphatidylinositol
(4,5)-bisphosphate (PIP
2
). Recently, stimulation of PLD activity by ARF6 has
