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Vol. 11, Issue 4, 1315-1327, April 2000
/KIAA0400, Bearing an
ADP-Ribosylation Factor GTPase-activating Protein Activity, Is
Involved in Paxillin Recruitment to Focal Adhesions and Cell
Migration
§
*Department of Molecular Biology, Osaka Bioscience Institute,
Suita, Osaka 565-0874, Japan; Paxillin acts as an adaptor molecule in integrin
signaling. Paxillin is localized to focal contacts but seems to also
exist in a relatively large cytoplasmic pool. Here, we report the
identification of a new paxillin-binding protein, PAG3
(paxillin-associated protein with ADP-ribosylation factor [ARF]
GTPase-activating protein [GAP] activity, number 3), which is
involved in regulation of the subcellular localization of paxillin.
PAG3 bound to all paxillin isoforms and was induced during monocyte
maturation, at which time paxillin expression is also increased and
integrins are activated. PAG3 was diffusely distributed in the
cytoplasm in premature monocytes but became localized at cell periphery
in mature monocytes, a fraction of which then colocalized with
paxillin. PAG3, on the other hand, did not accumulate at focal adhesion
plaques, suggesting that PAG3 is not an integrin
assembly protein. PAG3 was identical to KIAA0400/PapDepartment of Physiological
Sciences, School of Life Science, The Graduate University for Advanced
Studies, Okazaki, Aichi 444-8585, Japan; Graduate School
of Biostudies, Kyoto University, Sakyoku, Kyoto 606-8502, Japan; and
§Precursory Research for Embryonic Science and Technology,
Japan Science and Technology Corporation, Kyoto 619-0237, Japan
,
which was previously identified as a Pyk2-binding protein bearing a GAP
activity toward several ARFs in vitro. Mammalian ARFs fall into three
classes, and we showed that all classes could affect subcellular
localization of paxillin. We also examined possible interaction of PAG3
with ARFs and showed evidence that at least one of them, ARF6, seems to
be an intracellular substrate for GAP activity of PAG3. Moreover,
overexpression of PAG3, but not its GAP-inactive mutant, inhibited
paxillin recruitment to focal contacts and hampered cell migratory
activities, whereas cell adhesion activities were almost unaffected.
Therefore, our results demonstrate that paxillin recruitment to focal
adhesions is not mediated by simple cytoplasmic diffusion; rather, PAG3 appears to be involved in this process, possibly through its GAP activity toward ARF proteins. Our result thus delineates a new aspect
of regulation of cell migratory activities.
Corresponding author. E-mail address:
sabe{at}obi.or.jp.
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