Xenopus p21-activated kinase 5 regulates blastomere adhesive properties during convergent extension movements

Centre de Recherches en Biochimie Macromoléculaire, FRE 2593 CNRS, 34293 Montpellier, France.
Developmental Biology (Impact Factor: 3.55). 02/2005; 277(2):472-92. DOI: 10.1016/j.ydbio.2004.10.005
Source: PubMed


The p21-activated kinase (PAK) proteins regulate many cellular events including cell cycle progression, cell death and survival, and cytoskeleton rearrangements. We previously identified X-PAK5 that binds the actin and microtubule networks, and could potentially regulate their coordinated dynamics during cell motility. In this study, we investigated the functional importance of this kinase during gastrulation in Xenopus. X-PAK5 is mainly expressed in regions of the embryo that undergo extensive cell movements during gastrula such as the animal hemisphere and the marginal zone. Expression of a kinase-dead mutant inhibits convergent extension movements in whole embryos and in activin-treated animal cap by modifying behavior of cells. This phenotype is rescued in embryo by adding back X-PAK5 catalytic activity. The active kinase decreases cell adhesiveness when expressed in animal hemisphere and inhibits the calcium-dependent reassociation of cells, while dead X-PAK5 kinase localizes to cell-cell junctions and increases cell adhesion. In addition, endogenous X-PAK5 colocalizes with adherens junction proteins and its activity is regulated by extracellular calcium. Taken together, our results suggest that X-PAK5 regulates convergent extension movements in vivo by modulating the calcium-mediated cell-cell adhesion.

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Available from: Pascal de Santa Barbara, Aug 11, 2014
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    • "Interestingly, Mbt, a Drosophila PAK protein that shares close homology with human group II PAKs, localizes at adherens junctions when activated, and has been reported to induce the breakdown of these junctions during eye maturation [33]. In addition, the Xenopus PAK4 homologue, X-PAK5, also localizes at sites of cell contact and has been implicated in the cell–cell dissociation process [9]. We would speculate that in both of these instances the functionality could be related to PAK6 rather than other group II proteins. "
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    ABSTRACT: p-21 activated 6 (PAK6), first identified as interacting with the androgen receptor (AR), is over-expressed in multiple cancer tissues and has been linked to the progression of prostate cancer, however little is known about PAK6 function in the absence of AR signaling. We report here that PAK6 is specifically required for carcinoma cell–cell dissociation downstream of hepatocyte growth factor (HGF) for both DU145 prostate cancer and HT29 colon cancer cells. Moreover, PAK6 overexpression can drive cells to escape from adhesive colonies in the absence of stimulation. We have localized PAK6 to cell–cell junctions and have detected a direct interaction between the kinase domain of PAK6 and the junctional protein IQGAP1. Co-expression of IQGAP1 and PAK6 increases cell colony escape and leads to elevated PAK6 activation. Further studies have identified a PAK6/E-cadherin/IQGAP1 complex downstream of HGF. Moreover, we find that β-catenin is also localized with PAK6 in cell–cell junctions and is a novel PAK6 substrate. We propose a unique role for PAK6, independent of AR signaling, where PAK6 drives junction disassembly during HGF-driven cell–cell dissociation via an IQGAP1/E-cadherin complex that leads to the phosphorylation of β-catenin and the disruption of cell–cell adhesions. Electronic supplementary material The online version of this article (doi:10.1007/s00018-013-1528-5) contains supplementary material, which is available to authorized users.
    Full-text · Article · Dec 2013 · Cellular and Molecular Life Sciences CMLS
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    • "xPAK5 can bind to both actin and microtubule networks and can regulate their coordinated dynamics during cell motility. Endogenous xPAK5 co-localizes with adherens junction proteins, and its activity is regulated by extracellular calcium (Faure et al., 2005). xPAK5 also cooperates with Inca (induced in neural crest by AP2) protein, which is upregulated in Xenopus embryos in cytoskeletal restructuring and cell adhesion regulation during early embryo development (Luo et al., 2007). "
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    ABSTRACT: The p21-activated kinases (PAKs) are signaling nodes that play a crucial role in cellular processes including cell motility, differentiation, survival, gene transcription, and hormone signaling. PAKs are highly conserved family of serine-threonine kinases that act as effector for small GTPases Rac and Cdc42. Most of our knowledge about PAK functions has been derived from genetic approaches in lower organisms and many of these functions are similar to that seen in mammalian cells. In this review, we have summarized the extensive information generated in lower eukaryotes and very briefly discussed the current status of PAKs in humans.
    Full-text · Article · Jul 2009 · Journal of Cellular Biochemistry
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    • "In the early embryo, xPak1 is ubiquitously expressed at the mRNA and protein level, respectively, and both maternally and zygotically (Islam et al., 2000). Likewise, xPak2 and xPak3 are expressed maternally and throughout early development (Cau et al., 2000; Souopgui et al., 2002; Faure et al., 2005). At oocyte maturation, isolated xPak1 kinase domain, but not the N-terminal domain, interferes with xPak2 function (Faure et al., 1997; Cau et al., 2000), suggesting some degree of redundancy. "
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    ABSTRACT: The p21 activated kinases (Paks) are prominently involved in the regulation of cell motility. Using a kinase-dead mutant of xPak1, we show that during Xenopus gastrulation, the kinase activity of Pak1 is required upstream of Cdc42 for the establishment of cell polarity in the migrating mesendoderm. Overactivation of Pak1 function by the expression of constitutively active xPak1 compromises the maintenance of cell polarity, by indirectly inhibiting RhoA function. Inhibition of cell polarization does not affect the migration of single mesendoderm cells. However, Pak1 inhibition interferes with the guidance of mesendoderm migration by directional cues residing in the extracellular matrix of the blastocoel roof, and with mesendoderm translocation in the embryo.
    Preview · Article · Jul 2009 · Developmental Dynamics
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