Conditional knockout of polarity complex (atypical) PKCι reveals an anti-inflammatory function mediated by NF-κB

Forteza, Radia; Terán-Figueroa, Yolanda; Mashukova, Anastasia; Dulam, Vipin; Salas, Pedro J.

doi:10.1091/mbc.e16-02-0086

Cited by 8 publications

(18 citation statements)

References 75 publications

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“…Loss of the NF-κB subunit p65 impaired immune cell recruitment during Ras-mediated skin carcinogenesis [ 28 ]. Both aPKCλ and Par3 have been implicated in NF-κB signaling even though conflicting data exist whether they exert inhibitory or activating signals controlling NF-κB and immune responses [ 29 , 30 ]. Interestingly, DMBA-treated Par3 eKO, aPKCλ eKO, and edKO mice displayed an increased number of nuclear pS468-p65-positive cells, indicative of reduced NF-κB signaling [ 31 ], as well as reduced total p65 protein levels, albeit only statistically significant for aPKCλ eKO and edKO mice, with no significant changes in non-treated skin (Fig.…”

Section: Resultsmentioning

confidence: 99%

Shared and independent functions of aPKCλ and Par3 in skin tumorigenesis

et al. 2018

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The polarity proteins Par3 and aPKC are key regulators of processes altered in cancer. Par3/aPKC are thought to dynamically interact with Par6 but increasing evidence suggests that aPKC and Par3 also exert complex-independent functions. Whereas aPKCλ serves as tumor promotor, Par3 can either promote or suppress tumorigenesis. Here we asked whether and how Par3 and aPKCλ genetically interact to control two-stage skin carcinogenesis. Epidermal loss of Par3, aPKCλ, or both, strongly reduced tumor multiplicity and increased latency but inhibited invasion to similar extents, indicating that Par3 and aPKCλ function as a complex to promote tumorigenesis. Molecularly, Par3/aPKCλ cooperate to promote Akt, ERK and NF-κB signaling during tumor initiation to sustain growth, whereas aPKCλ dominates in promoting survival. In the inflammatory tumorigenesis phase Par3/aPKCλ cooperate to drive Stat3 activation and hyperproliferation. Unexpectedly, the reduced inflammatory signaling did not alter carcinogen-induced immune cell numbers but reduced IL-4 Receptor-positive stromal macrophage numbers in all mutant mice, suggesting that epidermal aPKCλ and Par3 promote a tumor-permissive environment. Importantly, aPKCλ also serves a distinct, carcinogen-independent role in controlling skin immune cell homeostasis. Collectively, our data demonstrates that Par3 and aPKCλ cooperate to promote skin tumor initiation and progression, likely through sustaining growth, survival, and inflammatory signaling.

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Section: Resultsmentioning

confidence: 99%

Shared and independent functions of aPKCλ and Par3 in skin tumorigenesis

et al. 2018

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“…, 2018 ). Intriguingly, and in apparent contradiction with an extensive body of literature in tissue culture cells and model organisms, the PKCι/λ conditional knockout phenotype does not show major loss of epithelial polarity in the intestine ( Forteza et al. , 2016 ).…”

Section: Introductionmentioning

confidence: 92%

“…Our lab made the intriguing observation that under NF-kB/IFN stimulation by extracellular TNFα (tumor necrosis factor) and IFNγ, intestinal epithelial cells posttranslationally down-regulate aPKC ( Mashukova et al. , 2011 ; Forteza et al. , 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…Using conditional ablation of PKCι/λ in the intestinal epithelium (Prkci flox/flox x Villin-CRE) in independently derived animal models, we and others showed that loss of function of aPKC in epithelia results in chronic intestinal inflammation ( Calcagno et al. , 2011 ; Forteza et al. , 2016 ), mediated by a Th17 response ( Nakanishi et al.…”

Section: Introductionmentioning

confidence: 99%

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The cell polarity kinase Par1b/MARK2 activation selects specific NF-kB transcripts via phosphorylation of core mediator Med17/TRAP80

Mashukova

Forteza

Shah

et al. 2021

MBoC

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Par1b/MARK2 is a Ser/Thr kinase with pleiotropic effects which participates in the generation of apico-basal polarity in C. elegans. It is phosphorylated by atypical PKC(ι/λ) in Thr595 and inhibited. Because previous work showed a decrease in aPKC activity under pro-inflammatory conditions, we analyzed the hypothesis that resulting decrease in Thr595-MARK2 with increased kinase activity may also participate in innate immunity. We confirmed that pT595-MARK2 was decreased under inflammatory stimulation. Increase in MARK2 activity was verified by Par3 delocalization and rescue with a specific inhibitor. MARK2 overexpression significantly enhanced the transcriptional activity of NF-kB for a subset of transcripts. It also resulted in phosphorylation of a single band (∼Mr 80,000) coimmunoprecipitating with RelA, identified as Med17. In vitro phosphorylation showed direct phosphorylation of Med17 in Ser152 by recombinant MARK2. Expression of S152D-Med17 mimicked the effect of MARK2 activation on downstream transcriptional regulation, which was antagonized by S152A-Med17. Decrease in pThr595 phosphorylation was validated in aPKC-deficient mouse jejunal mucosae. The transcriptional effects were confirmed in transcriptome analysis and transcript enrichment determinations in cells expressing S152D-Med17. We conclude that the axis MARK2- Med17 represents a novel form of crosstalk between polarity signaling and transcriptional regulation including, but not restricted to, innate immunity responses.

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“…In the Goto-Kakizaki (GK) type 2 diabetic rat model, activity of the atypical PKC ζ which phosphorylates ROCK 27 is regulated early in the retina 28 and interaction of PKC ζ with RhoA is required for LPS-induced blood-brain barrier breakdown 29 suggesting that Rho-kinases could intervene in retinal barriers alteration in the diabetic retina. But, the early consequences of diabetes on ROCK-1-induced cytoskeleton regulations remain imperfectly understood.…”

Section: Introductionmentioning

confidence: 99%

ROCK-1 mediates diabetes-induced retinal pigment epithelial and endothelial cell blebbing: Contribution to diabetic retinopathy

Rothschild

Salah

Berdugo

et al. 2017

Sci Rep

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In diabetic retinopathy, the exact mechanisms leading to retinal capillary closure and to retinal barriers breakdown remain imperfectly understood. Rho-associated kinase (ROCK), an effector of the small GTPase Rho, involved in cytoskeleton dynamic regulation and cell polarity is activated by hyperglycemia. In one year-old Goto Kakizaki (GK) type 2 diabetic rats retina, ROCK-1 activation was assessed by its cellular distribution and by phosphorylation of its substrates, MYPT1 and MLC. In both GK rat and in human type 2 diabetic retinas, ROCK-1 is activated and associated with non-apoptotic membrane blebbing in retinal vessels and in retinal pigment epithelium (RPE) that respectively form the inner and the outer barriers. Activation of ROCK-1 induces focal vascular constrictions, endoluminal blebbing and subsequent retinal hypoxia. In RPE cells, actin cytoskeleton remodeling and membrane blebs in RPE cells contributes to outer barrier breakdown. Intraocular injection of fasudil, significantly reduces both retinal hypoxia and RPE barrier breakdown. Diabetes-induced cell blebbing may contribute to ischemic maculopathy and represent an intervention target.

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Conditional knockout of polarity complex (atypical) PKCι reveals an anti-inflammatory function mediated by NF-κB

Abstract: Atypical PKC, Par6, and Par3 constitute a conserved complex signaling cell asymmetry. In contrast to its role in other tissues, atypical PKC inhibits NF-κB activation in epithelia and may function in maintaining low levels of inflammation in addition to establishing apicobasal polarity.

Cited by 8 publications

References 75 publications

Shared and independent functions of aPKCλ and Par3 in skin tumorigenesis

Shared and independent functions of aPKCλ and Par3 in skin tumorigenesis

The cell polarity kinase Par1b/MARK2 activation selects specific NF-kB transcripts via phosphorylation of core mediator Med17/TRAP80

ROCK-1 mediates diabetes-induced retinal pigment epithelial and endothelial cell blebbing: Contribution to diabetic retinopathy

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