Local phosphocycling mediated by LOK/SLK restricts ezrin function to the apical aspect of epithelial cells

Viswanatha, Raghuvir; Ohouo, Patrice; Smolka, Marcus B.; Bretscher, Anthony

doi:10.1083/jcb.201207047

Cited by 101 publications

(210 citation statements)

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“…The kinases Akt2, LOK and SLK, which have been implicated in phosphorylation of ezrin, localize to the apical plasma membrane domain (Shiue et al, 2005;Viswanatha et al, 2012). For other kinases, the localization is less clear.…”

Section: Resultsmentioning

confidence: 99%

“…Various kinases can phosphorylate ezrin and stimulate microvilli development in intestinal epithelial cells and, evidently, these kinases need to be in close proximity to ezrin. Some of these kinases, such as LOK, SLK and Akt2, have been demonstrated to localize in the microvilli membrane at the apical surface (Shiue et al, 2005;Viswanatha et al, 2012), whereas the localization of other kinases, notably aPKCi and Mst4, was not clear. Here, we demonstrated that aPKCi-T555 (as well as its activating kinase PDK1) and Mst4, previously demonstrated to contribute to apical T567 phosphorylation and localization of ezrin and consequently to apical microvilli formation in intestinal epithelial cells (Wald et al, 2008;ten Klooster et al, 2009;Gloerich et al, 2012), did not localize predominantly to the apical surface.…”

Section: Discussionmentioning

confidence: 99%

“…Several kinases have been implicated in the direct T567 phosphorylation of ezrin in intestinal epithelial cells, including protein kinase B2/Akt2 (Shiue et al, 2005), atypical protein kinase C-iota (aPKCi) (Wald et al, 2008), mammalian Sterile 20 (Ste20)-like kinase-4 (Mst4) (Gloerich et al, 2012;ten Klooster et al, 2009), lymphocyte-oriented kinase (LOK) and Ste20-like kinase (SLK) (Viswanatha et al, 2012). Knockdown of each of these kinases in various intestinal epithelial cell models inhibits microvillus development at the apical plasma membrane (Gloerich et al, 2012;Shiue et al, 2005;ten Klooster et al, 2009;Viswanatha et al, 2012;Wald et al, 2008). Some of these kinases have been reported to localize to the apical microvillus membrane (Shiue et al, 2005;Viswanatha et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Knockdown of each of these kinases in various intestinal epithelial cell models inhibits microvillus development at the apical plasma membrane (Gloerich et al, 2012;Shiue et al, 2005;ten Klooster et al, 2009;Viswanatha et al, 2012;Wald et al, 2008). Some of these kinases have been reported to localize to the apical microvillus membrane (Shiue et al, 2005;Viswanatha et al, 2012). By contrast, other ezrin-phosphorylating kinases appear to, at least partially, localize to undefined intracellular compartments.…”

Section: Introductionmentioning

confidence: 99%

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Myosin Vb and rab11a regulate ezrin phosphorylation in enterocytes

Dhekne

Hsiao

Roelofs

et al. 2014

Journal of Cell Science

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Microvilli at the apical surface of enterocytes allow the efficient absorption of nutrients in the intestine. Ezrin activation by its phosphorylation at T567 is important for microvilli development, but how such ezrin phosphorylation is controlled is not well understood. We demonstrate that a subset of kinases that phosphorylate ezrin closely co-distributes with apical recycling endosome marker Rab11a in the subapical domain. Expression of dominant-negative Rab11a mutant or depletion of the Rab11a-binding motor protein myosin Vb prevents the subapical enrichment of Rab11a and these kinases and inhibits ezrin phosphorylation and microvilli development, without affecting the polarized distribution of ezrin itself. We observe a similar loss of the subapical enrichment of Rab11a and the kinases and reduced phosphorylation of ezrin in microvillus inclusion disease, which is associated with MYO5B mutations, intestinal microvilli atrophy and malabsorption. Thus, part of the machinery for ezrin activation depends on recycling endosomes controlled by myosin Vb and Rab11a which, we propose, might act as subapical signaling platforms that enterocytes use to regulate development of microvilli and maintain human intestinal function.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Myosin Vb and rab11a regulate ezrin phosphorylation in enterocytes

Dhekne

Hsiao

Roelofs

et al. 2014

Journal of Cell Science

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“…LOK deficiency also leads to increased LFA-1-mediated lymphocyte adhesion (11). In epithelial cells, localized ezrin phosphorylation by LOK contributes to restricted formation of microvilli at the apical surface (12).…”

mentioning

confidence: 99%

Caspase Cleavages of the Lymphocyte-oriented Kinase Prevent Ezrin, Radixin, and Moesin Phosphorylation during Apoptosis

Leroy

Belkina

Long

et al. 2016

Journal of Biological Chemistry

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The lymphocyte-oriented kinase (LOK), also called serine threonine kinase 10 (STK10), is synthesized mainly in lymphocytes. It is involved in lymphocyte migration and polarization and can phosphorylate ezrin, radixin, and moesin (the ERM proteins). In a T lymphocyte cell line and in purified human lymphocytes, we found LOK to be cleaved by caspases during apoptosis. The first cleavage occurs at aspartic residue 332, located between the kinase domain and the coiled-coil regulation domain. This cleavage generates an N-terminal fragment, p50 N-LOK, containing the kinase domain and a C-terminal fragment, which is further cleaved during apoptosis. Although these cleavages preserve the entire kinase domain, p50 N-LOK displays no kinase activity. In apoptotic lymphocytes, caspase cleavages of LOK are concomitant with a decrease in ERM phosphorylation. When non-apoptotic lymphocytes from mice with homozygous and heterozygous LOK knockout were compared, the latter showed a higher level of ERM phosphorylation, but when apoptosis was induced, LOK ؊/؊ and LOK ؉/؊ lymphocytes showed the same low level, confirming in vivo that LOK-induced ERM phosphorylation is prevented during lymphocyte apoptosis. Our results demonstrate that cleavage of LOK during apoptosis abolishes its kinase activity, causing a decrease in ERM phosphorylation, crucial to the role of the ERM proteins in linking the plasma membrane to actin filaments.

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Histone H3K18 and Ezrin Lactylation Promote Renal Dysfunction in Sepsis‐Associated Acute Kidney Injury

Qiao,

Tan,

Liu

et al. 2024

Advanced Science

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Histone lactylation is a metabolic stress‐related histone modification. However, the role of histone lactylation in the development of sepsis‐associated acute kidney injury (SA‐AKI) remains unclear. Here, histone H3K18 lactylation (H3K18la) is elevated in SA‐AKI, which is reported in this study. Furthermore, this lactate‐dependent histone modification is enriched at the promoter of Ras homolog gene family member A (RhoA) and positively correlated with the transcription. Correction of abnormal lactate levels resulted in a reversal of abnormal histone lactylation at the promoter of RhoA. Examination of related mechanism revealed that histone lactylation promoted the RhoA/Rho‐associated protein kinase (ROCK) /Ezrin signaling, the activation of nuclear factor‐κB (NF‐κB), inflammation, cell apoptosis, and aggravated renal dysfunction. In addition, Ezrin can undergo lactylation modification. Multiple lactylation sites are identified in Ezrin and confirmed that lactylation mainly occurred at the K263 site. The role of histone lactylation is revealed in SA‐AKI and reportes a novel post‐translational modification in Ezrin. Its potential role in regulating inflammatory metabolic adaptation of renal proximal tubule epithelial cells is also elucidated. The results provide novel insights into the epigenetic regulation of the onset of SA‐AKI.

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Local phosphocycling mediated by LOK/SLK restricts ezrin function to the apical aspect of epithelial cells

Abstract: Local cycling of LOK/SLK-dependent phosphorylation of ezrin is required for its apical localization and for microvillus formation.

Cited by 101 publications

References 61 publications

Myosin Vb and rab11a regulate ezrin phosphorylation in enterocytes

Myosin Vb and rab11a regulate ezrin phosphorylation in enterocytes

Caspase Cleavages of the Lymphocyte-oriented Kinase Prevent Ezrin, Radixin, and Moesin Phosphorylation during Apoptosis

Histone H3K18 and Ezrin Lactylation Promote Renal Dysfunction in Sepsis‐Associated Acute Kidney Injury

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