FAK phosphorylation at Tyr-925 regulates cross-talk between focal adhesion turnover and cell protrusion

Deramaudt, Thérèse B.; Dujardin, Denis; Hamadi, Abdelkader; Noulet, Fanny; Kolli, K. Pallav; Mey, J. De; Takeda, Kenneth; Rondé, Philippe

doi:10.1091/mbc.e10-08-0725

Cited by 118 publications

(128 citation statements)

References 71 publications

(84 reference statements)

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“…Moreover, the localization and activation of protein kinases may require the involvement of an intermediate scaffolding/adaptor protein [49]. For example, although targeting of FAK to focal adhesions does not absolutely require an association with paxillin, its phosphorylation by Src at Y576/577 and consequently Y925, does [66,67].…”

Section: Kinase-substrate Specificitymentioning

confidence: 99%

“…Although paxillin binding is not absolutely necessary for FAK subcellular localization, it is recognized as being the major mechanism by which FAK is not only targeted to sites of focal adhesions, but presented to kinases like Src for full activation [30,51,67]. However, without paxillin binding, FAK cannot be phosphorylated at Y576/Y577 and consequently Y925, which negatively regulates cell migration [66,67].…”

Section: Paxillin Structure and Functionmentioning

confidence: 99%

“…However, without paxillin binding, FAK cannot be phosphorylated at Y576/Y577 and consequently Y925, which negatively regulates cell migration [66,67]. Conversely, paxillin-mediated focal adhesion disassembly and cell migration, which requires paxillin tyrosine phosphorylation by both FAK and Src, cannot occur without the binding of paxillin to activated FAK (Y925) [66,109].…”

Section: Paxillin Structure and Functionmentioning

confidence: 99%

“…Studies involving paxillin null fibroblasts demonstrate that while paxillin is not critically necessary for the localization of FAK to focal adhesions, an interaction between FAK and paxillin is required for the proper activation of the kinase [30,51,67]. Specifically, in the absence of this association, FAK is still capable of undergoing Y397 autophosphorylation upon integrin engagement, but shows altered Src-mediated phosphorylation at Y567 and Y577 [66,67].…”

Section: Paxillin S250 Is Required For Paxillin-fak Associationmentioning

confidence: 99%

“…Specifically, in the absence of this association, FAK is still capable of undergoing Y397 autophosphorylation upon integrin engagement, but shows altered Src-mediated phosphorylation at Y567 and Y577 [66,67]. This, in turn, prevents subsequent phosphorylation of FAK, in particular Y925, which is necessary for the induction of focal adhesion disassembly [66,67]. paxillin S250T mutant (Figure 5.3).…”

Section: Paxillin S250 Is Required For Paxillin-fak Associationmentioning

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: Kinase-substrate Specificitymentioning

confidence: 99%

Section: Paxillin Structure and Functionmentioning

confidence: 99%

Section: Paxillin Structure and Functionmentioning

confidence: 99%

Section: Paxillin S250 Is Required For Paxillin-fak Associationmentioning

confidence: 99%

Section: Paxillin S250 Is Required For Paxillin-fak Associationmentioning

confidence: 99%

See 3 more Smart Citations

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

Baron

et al. 2012

Oncogene

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The molecular mechanism by which saturated lysophosphatidylcholine attenuates the metastatic capacity of melanoma cells

et al. 2016

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Lysophophatidylcholine (Lyso PC ) is an abundant constituent in human plasma. Patients with malignant cancer diseases have attenuated Lyso PC plasma levels, and thus Lyso PC has been examined as a metabolic biomarker for cancer prediction. Preclinical studies have shown that solid tumor cells drastically degrade Lyso PC s by incorporating their free fatty acids into cell membrane phospholipids. In this way, Lyso PC C18:0 reduced the metastatic spread of murine melanoma B16.F10 cells in mice. Although membrane rigidification may have a key role in the attenuation of metastasis, evidence for this has yet to be shown. Therefore, the present study aimed to determine how Lyso PC reduces the metastatic capacity of B16.F10 cells. Following cellular preincubation with Lyso PC C18:0 at increasing concentrations and lengths of time, cell migration was most significantly attenuated with 450 μ m Lyso PC C18:0 at 72 h. Biosensor measurements suggest that, despite their abundance in B16.F10 cells, Lyso PC ‐sensitive G protein‐coupled receptors do not appear to contribute to this effect. Instead, the attenuated migration appears to result from changes in cell membrane properties and their effect on underlying signaling pathways, most likely the formation of focal adhesion complexes. Treatment with 450 μ m Lyso PC C18:0 activates protein kinase C ( PKC )δ to phosphorylate syndecan‐4, accompanied by deactivation of PKC α. Subsequently, focal adhesion complex formation was attenuated, as confirmed by the reduced activity of focal adhesion kinase ( FAK ). Interestingly, 450 μ m Lyso PC C18:1 did not affect FAK activity, explaining its lower propensity to affect migration and metastasis. Therefore, membrane rigidification by Lyso PC C18:0 appears to prevent the formation of focal adhesion complexes, thus affecting integrin activity as a key for metastatic melanoma spread.

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Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast Cancer

Prever

Hsu

et al. 2022

Advanced Science

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Breast cancer is the most prevalent cancer and a major cause of death in women worldwide. Although early diagnosis and therapeutic intervention significantly improve patient survival rate, metastasis still accounts for most deaths. Here it is reported that, in a cohort of more than 2000 patients with breast cancer, overexpression of PI3KC2α occurs in 52% of cases and correlates with high tumor grade as well as increased probability of distant metastatic events, irrespective of the subtype. Mechanistically, it is demonstrated that PI3KC2α synthetizes a pool of PI(3,4)P2 at focal adhesions that lowers their stability and directs breast cancer cell migration, invasion, and metastasis. PI(3,4)P2 locally produced by PI3KC2α at focal adhesions recruits the Ras GTPase activating protein 3 (RASA3), which inactivates R‐RAS, leading to increased focal adhesion turnover, migration, and invasion both in vitro and in vivo. Proof‐of‐concept is eventually provided that inhibiting PI3KC2α or lowering RASA3 activity at focal adhesions significantly reduces the metastatic burden in PI3KC2α‐overexpressing breast cancer, thereby suggesting a novel strategy for anti‐breast cancer therapy.

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FAK phosphorylation at Tyr-925 regulates cross-talk between focal adhesion turnover and cell protrusion

Abstract: FAK plays a key role in the regulation of cell migration. The authors show that the phosphorylation status of FAK at Tyr-925 is involved in FA turnover, formation of FAs, and increase in cell edge protrusion, together with activation of the p130CAS/Rac1 signaling pathway.

Cited by 118 publications

References 71 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

The molecular mechanism by which saturated lysophosphatidylcholine attenuates the metastatic capacity of melanoma cells

Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast Cancer

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