Paxillin-Y118 phosphorylation contributes to the control of Src-induced anchorage-independent growth by FAK and adhesion

Sachdev, Sanjay; Bu, Yahao; Gelman, Irwin H.

doi:10.1186/1471-2407-9-12

Cited by 53 publications

(46 citation statements)

References 63 publications

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“…FAK, and the related protein, CAKβ/Pyk2/CadTK/RAFTK, have not only been shown to physically interact and co-localize with paxillin in vivo, but the activation and/or overexpression of these tyrosine kinases has been implicated in an increased proportion of tyrosine phosphorylated paxillin [86,111,112]. Specifically, studies have shown that the relative levels of paxillin Y31 and Y118 phosphorylation are reduced in FAK -/-MEFs in comparison to wildtype FAK +/+, with additional studies demonstrating complete inhibition of paxillin tyrosine phosphorylation via overexpression of dominant negative FAK; inflated levels of paxillin tyrosine phosphorylation in the FAK -/-is believed to be the result of the compensatory expression of CAKβ in these cells [83,86,109].…”

Section: Paxillin Tyrosine Phosphorylationmentioning

confidence: 99%

“…Differential paxillin phosphorylation within the focal adhesion has been shown to mediate focal adhesion assembly and disassembly [139,140]. Specifically, serine phosphorylation of the LIM domain of paxillin has been found to temporally target and/or regulate the integration of paxillin into focal adhesions while tyrosine phosphorylated paxillin has been shown to recruit the focal adhesion proteins FAK and Src into the adhesion complex [99,110,111]. Actively disassembling adhesions, such as early adhesions and the distal part of late adhesions, are preferential zones of microtubule targeting and catastrophe that have been shown to be enriched in phosphorylated paxillin [22,30,110,140].…”

Section: Autorad Chaptermentioning

confidence: 99%

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SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

Baron

et al. 2012

Oncogene

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Section: Paxillin Tyrosine Phosphorylationmentioning

confidence: 99%

Section: Autorad Chaptermentioning

confidence: 99%

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

Baron

et al. 2012

Oncogene

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“…Paxillin dynamics are regulated by several proteins including FAK [22][23][24]. We previously showed that both paxillin and FAK were rapidly phosphorylated following leukocyte adhesion under flow conditions [19] and we and others have also shown that FAK redistributes during neutrophil transmigration [18] (Supporting Information Fig.…”

Section: Disrupting Fak and Fak Signaling Blocks Neutrophil Transmigrmentioning

confidence: 99%

Endothelial paxillin and focal adhesion kinase (FAK) play a critical role in neutrophil transmigration

et al. 2012

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CanadaDuring an inflammatory response, endothelial cells undergo morphological changes to allow for the passage of neutrophils from the blood vessel to the site of injury or infection. Although endothelial cell junctions and the cytoskeleton undergo reorganization during inflammation, little is known about another class of cellular structures, the focal adhesions. In this study, we examined several focal adhesion proteins during an inflammatory response. We found that there was selective loss of paxillin and focal adhesion kinase (FAK) from focal adhesions in proximity to transmigrating neutrophils; in contrast the levels of the focal adhesion proteins b1-integrin and vinculin were unaffected. Paxillin was lost from focal adhesions during neutrophil transmigration both under static and flow conditions. Down-regulating endothelial paxillin with siRNA blocked neutrophil transmigration while having no effect on rolling or adhesion. As paxillin dynamics are regulated partly by FAK, the role of FAK in neutrophil transmigration was examined using two complementary methods. siRNA was used to down-regulate total FAK protein while dominant-negative, kinase-deficient FAK was expressed to block FAK signaling. Disruption of the FAK protein or FAK signaling decreased neutrophil transmigration. Collectively, these findings reveal a novel role for endothelial focal adhesion proteins paxillin and FAK in regulating neutrophil transmigration. IntroductionNeutrophils are essential mediators of host defense. During inflammation, neutrophils leave the bloodstream and traffic into the tissue in a well-described series of steps [1,2]. The molecular interactions governing the initial stages of tethering, rolling and firm adhesion have been well studied [1,2], whereas a clear picture of the latter steps underlying the passage of the leukocytes through the blood vessel has been slower to emerge [3][4][5].During transmigration endothelial cells undergo rapid changes in their structural organization [5,6]. For example, the junctional protein vascular endothelial cadherin (VE-cadherin) is phosphorylated and redistributes during neutrophil transmigration [7][8][9]. This results in the formation of transient gaps that 436allow for the passage of neutrophils [9]. Platelet endothelial cell adhesion molecule-1 (PECAM-1), another junctional protein, is regulated by the action of the kinesins and requires an intact microtubule cytoskeleton to enable PECAM-1 recycling from membrane compartments to the lateral junctions [10]. In the absence of PECAM-1 recycling, leukocyte transmigration is arrested [10]. Cortactin-mediated rearrangement of the actin cytoskeleton [7] and intermediate filaments [11] is also critical for successful transmigration. Overall, these results reveal that endothelial cells are active participants in transmigration.The importance of cytoskeletal and junctional proteins during leukocyte transmigration led us to ask whether another class of cellular structures, the focal adhesions, also play a role during this process. Focal a...

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“…To test adhesion of ECs to ECM after in vivo Cdc42 depletion, we assessed the focal adhesion marker phosphorylated Paxillin ( pPax, Y118; pPxn -Mouse Genome Informatics) (Sachdev et al, 2009). Cdc42…”

Section: Cdc42 Regulates Ec Adhesionmentioning

confidence: 99%

Cdc42 is required for cytoskeletal support of endothelial cell adhesion during blood vessel formation

Barry

Meadows

et al. 2015

Development

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The Rho family of small GTPases has been shown to be required in endothelial cells (ECs) during blood vessel formation. However, the underlying cellular events controlled by different GTPases remain unclear. Here, we assess the cellular mechanisms by which Cdc42 regulates mammalian vascular morphogenesis and maintenance. In vivo deletion of Cdc42 in embryonic ECs (Cdc42 Tie2KO ) results in blocked lumen formation and endothelial tearing, leading to lethality of mutant embryos by E9-10 due to failed blood circulation. Similarly, inducible deletion of Cdc42 (Cdc42 Cad5KO ) at mid-gestation blocks angiogenic tubulogenesis. By contrast, deletion of Cdc42 in postnatal retinal vessels leads to aberrant vascular remodeling and sprouting, as well as markedly reduced filopodia formation. We find that Cdc42 is essential for organization of EC adhesion, as its loss results in disorganized cell-cell junctions and reduced focal adhesions. Endothelial polarity is also rapidly lost upon Cdc42 deletion, as seen by failed localization of apical podocalyxin (PODXL) and basal actin. We link observed failures to a defect in F-actin organization, both in vitro and in vivo, which secondarily impairs EC adhesion and polarity. We also identify Cdc42 effectors Pak2/4 and N-WASP, as well as the actomyosin machinery, to be crucial for EC actin organization. This work supports the notion of Cdc42 as a central regulator of the cellular machinery in ECs that drives blood vessel formation.

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Paxillin-Y118 phosphorylation contributes to the control of Src-induced anchorage-independent growth by FAK and adhesion

Cited by 53 publications

References 63 publications

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

Endothelial paxillin and focal adhesion kinase (FAK) play a critical role in neutrophil transmigration

Cdc42 is required for cytoskeletal support of endothelial cell adhesion during blood vessel formation

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