Atypical protein kinase C (iota) activates ezrin in the apical domain of intestinal epithelial cells

Wald, Flavia A.; Oriolo, Andrea S.; Mashukova, Anastasia; Fregien, Nevis; Langshaw, Amber; Salas, Pedro J.

doi:10.1242/jcs.016246

Cited by 65 publications

(70 citation statements)

References 53 publications

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“…Outside the setting of cancer, several kinases (PKC, ROCK, GRK2, p38, MRCK and so on) have been previously shown to contribute to the phosphorylation of ezrin (Matsui et al, 1998;Oshiro et al, 1998;Pietromonaco et al, 1998;Ng et al, 2001;Weng et al, 2005;Wald et al, 2008). Very recently, PKC phosphorylation of ezrin in androgen-primed prostate cancer cells was reported, lending further support to our hypothesis in metastasis (Chuan et al, 2006).…”

Section: Regulation Of Ezrin By Pkc L Ren Et Alsupporting

confidence: 81%

“…Several protein kinases have been found to phosphorylate the C-terminal threonine residue of ERM proteins. Examples include protein kinase Ca (PKCa) (Ng et al, 2001;Chuan et al, 2006), PKCy , PKCi (Wald et al, 2008), Rho kinases/ROCK (Matsui et al, 1998;Oshiro et al, 1998), G protein-coupled receptor kinase 2 (GRK2) (Cant and Pitcher, 2005) and myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK) (Nakamura et al, 2000). Most studies that have investigated the kinase responsible for ezrin T567 phosphorylation have been conducted in cell-free systems or non-cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

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The actin-cytoskeleton linker protein ezrin is regulated during osteosarcoma metastasis by PKC

et al. 2008

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Ezrin is a member of the ERM (ezrin, radixin, moesin) protein family and links F-actin to the cell membrane following phosphorylation. Ezrin has been associated with tumor progression and metastasis in several cancers including the pediatric solid tumors, osteosarcoma and rhabdomyosarcoma. In this study, we were surprised to find that ezrin was not constitutively phosphorylated but rather was dynamically regulated during metastatic progression in osteosarcoma. Metastatic osteosarcoma cells expressed phosphorylated ERM early after their arrival in the lung, and then late in progression, only at the invasive front of larger metastatic lesions. To pursue mechanisms for this regulation, we found that inhibitors of PKC (protein kinase C) blocked phosphorylation of ezrin, and that ezrin coimmunoprecipitated in cells with PKCa, PKCi and PKCc. Furthermore, phosphorylated forms of ezrin and PKC had identical expression patterns at the invasive front of pulmonary metastatic lesions in murine and human patient samples. Finally, we showed that the promigratory effects of PKC were linked to ezrin phosphorylation. These data are the first to suggest a dynamic regulation of ezrin phosphorylation during metastasis and to connect the PKC family members with this regulation.

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Section: Regulation Of Ezrin By Pkc L Ren Et Alsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

The actin-cytoskeleton linker protein ezrin is regulated during osteosarcoma metastasis by PKC

et al. 2008

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“…Interestingly, in contrast to total PKCl/i, we observed predominant nuclear localization of phospho-PKCl/i in all IDC samples (Figure 1d and Supplementary Figure S1b). As phosphorylation event (specifically at T555) is believed to prime activation of PKCl/i, 38 our observations indicate predominant localization of active PKCl/i in the nuclei of breast tumor cells and oppose the idea that inactive PKCl/i localizes within nuclei, as suggested earlier. 28 Next, we collected multiple human metastatic breast cancer samples (n ¼ 10) from distal organs such as the bone, brain, chest wall, colon, gallbladder, liver, lung and ovary to test PKCl/i expression and phosphorylation ( Figure 1e).…”

Section: Resultscontrasting

confidence: 63%

PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis

et al. 2014

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Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKCk/i, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKCk/i signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCk/i signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKCk/i expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKCk/i significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCk/i-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFb and IL1b could activate PKCk/i signaling in TNBC cells and depletion of PKCk/i impairs NF-jB p65 (RelA) nuclear localization. We observed that cytokine-PKCk/i-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKCk/i promote TNBC growth, invasion and metastasis. Thus, targeting PKCk/i signaling could be a therapeutic option for breast cancer, including the TNBC subtype.

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“…These results indicate that the expression of Abcc2 in the BBM does not require cPKC activity under basal conditions, whereas the decrease of p-ezrin and redistribution of Abcc2 after Thx treatment is mediated by the activation of cPKC. Multiple kinases (Matsui et al, 1998;Wald et al, 2008) and putative protein phosphatase(s) (Zhu et al, 2007) are involved in the phosphorylation and dephosphorylation of the C-terminal threonine of ERM proteins to regulate the balance between their active and inactive forms. PKC␣ classified into cPKC is one of the kinases that directly associates with ezrin to phosphorylate its C-terminal threonine (Thr567) as shown in 2C4 fibrosarcoma cells (Ng et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Correlation between Apical Localization of Abcc2/Mrp2 and Phosphorylation Status of Ezrin in Rat Intestine

Nakano

Sekine²,

Ito

et al. 2009

Drug Metab Dispos

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ABSTRACT:The multidrug resistance-associated protein 2/ATP-binding cassette transporter family C2 (Mrp2/Abcc2) is an ATP-dependent export pump that mediates the transport of a variety of organic anions. Abcc2 is mainly expressed on the canalicular membrane of hepatocytes and also the brush-border membrane of intestinal epithelial cells. We have previously reported that Abcc2 is rapidly internalized from the canalicular membrane during acute oxidative stress, which induces protein kinase C (PKC) activation in rat liver. However, it has not been elucidated whether PKC is involved in the regulation of Abcc2 localization in other tissues. In this study, we investigated this issue in rat intestinal epithelia. Exposure to thymeleatoxin, a conventional PKC (cPKC) activator, for 20 min reduced the cumulative glutathione S-bimane efflux for 40 min via Abcc2 from 30.3 ؎ 2.1 nmol/cm to 18.1 ؎ 1.6 nmol/cm. Likewise, the Abcc2 expression in the brush-border membrane of the small intestine was reduced to half that of the control without changing the total amount of Abcc2 present in the homogenate. Immunoprecipitation analysis suggested an interaction between Abcc2 and ezrin, a scaffolding protein that is dominantly expressed in the intestine. Thymeleatoxin treatment decreased the amount of the active form (C-terminally phosphorylated form) of ezrin and the amount of Abcc2 that coimmunoprecipitated with ezrin. These results indicate that cPKC activation diminishes the protein-protein interaction between ezrin and Abcc2. In conclusion, the phosphorylation status of ezrin correlates with the cell surface expression of Abcc2 in the rat small intestine, which may be regulated by cPKC.The small intestine is a highly differentiated organ with a barrier function against xenobiotics and a gateway function for nutrients. The ATP-binding cassette (ABC) transporter family, including P-glycoprotein/multidrug resistance protein 1 (P-gp/Mdr1/Abcb1), breast cancer resistant protein (Bcrp/Abcg2), and multidrug resistance-associated protein 2 (Mrp2/Abcc2), are well known efflux transporters that are located on the brush-border membrane (BBM) of small intestinal epithelia to limit the absorption of a broad range of compounds (Takano et al., 2006). The distinct but sometimes overlapping substrate specificities of these efflux transporters have been shown previously (Chan et al., 2004). Indeed, a significant increase in the oral absorption of their substrates, including drugs and carcinogens, was confirmed in animals genetically deficient in these transporters (Dietrich et al., 2001;Yamaguchi et al., 2002).Several reports indicated the disparity between mRNA and protein expression of Abcc2 in the intestine. Naud et al. (2007) reported that Abcc2 protein expression was reduced to approximately 40% of that of the control during chronic renal failure in rats, but its mRNA expression was unaffected. Dietrich et al. (2004) also reported ABCC2 protein expression was reduced to approximately 27% of that of the control patients in the human intestine du...

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Atypical protein kinase C (iota) activates ezrin in the apical domain of intestinal epithelial cells

Cited by 65 publications

References 53 publications

The actin-cytoskeleton linker protein ezrin is regulated during osteosarcoma metastasis by PKC

The actin-cytoskeleton linker protein ezrin is regulated during osteosarcoma metastasis by PKC

PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis

Correlation between Apical Localization of Abcc2/Mrp2 and Phosphorylation Status of Ezrin in Rat Intestine

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