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首页> 美国卫生研究院文献>Cell Regulation >A New Paxillin-binding Protein PAG3/Papα/KIAA0400 Bearing an ADP-Ribosylation Factor GTPase-activating Protein Activity Is Involved in Paxillin Recruitment to Focal Adhesions and Cell Migration
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A New Paxillin-binding Protein PAG3/Papα/KIAA0400 Bearing an ADP-Ribosylation Factor GTPase-activating Protein Activity Is Involved in Paxillin Recruitment to Focal Adhesions and Cell Migration

机译：一种新的Paxillin结合蛋白PAG3 /Papα/ KIAA0400具有ADP-核糖基化因子GTPase激活蛋白活性参与Paxillin募集以促进粘着和细胞迁移。

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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/Papα, 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.
机译：Paxillin在整联蛋白信号传导中充当衔接分子。 Paxillin定位于局部接触，但似乎也存在于相对较大的细胞质库中。在这里，我们报告鉴定新的paxillin结合蛋白PAG3（具有ADP-核糖基化因子[ARF] GTPase激活蛋白[GAP]活性，编号3的与paxillin相关的蛋白），该蛋白参与亚细胞定位的调节的paxillin。 PAG3与所有Paxillin亚型结合，并在单核细胞成熟过程中被诱导，此时Paxillin的表达也增加，整联蛋白被激活。 PAG3分散地分布在早熟单核细胞的细胞质中，但在成熟单核细胞中定位于细胞外围，然后一部分与帕西林共定位。另一方面，PAG3没有聚集在粘着斑上，表明PAG3不是整合素装配蛋白。 PAG3与KIAA0400 /Papα相同，后者先前被鉴定为Pyk2结合蛋白，在体外具有对几种ARF的GAP活性。哺乳动物的ARF分为三类，我们证明了所有这些类都可能影响Paxillin的亚细胞定位。我们还检查了PAG3与ARF的可能相互作用，并显示证据表明其中至少一个ARF6似乎是PAG3的GAP活性的细胞内底物。此外，PAG3的过表达，但不是其GAP失活的突变体，却抑制了Paxillin募集至局部接触并阻碍了细胞迁移活性，而细胞粘附活性几乎未受影响。因此，我们的研究结果表明，帕克西林募集到粘着斑不是由简单的细胞质扩散介导的。相反，PAG3可能通过其对ARF蛋白的GAP活性参与了这一过程。因此，我们的结果描述了细胞迁移活动调控的新方面。

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