Interaction between PAR-3 and the aPKC–PAR-6 complex is indispensable for apical domain development of epithelial cells

Horikoshi, Yosuke; Suzuki, Atsushi; Yamanaka, Tatsuhiko; Sasaki, Kazunori; Mizuno, Keiko; Sawada, Hajime; Yonemura, Shigenobu; Ohno, Shigeo

doi:10.1242/jcs.043174

Cited by 156 publications

(179 citation statements)

References 48 publications

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“…Studies using this system have uncovered the molecular basis of the opposing actions of PAR-3 and Lgl in epithelial cell polarity regulation (Horikoshi et al, 2009;Yamanaka et al, 2006Yamanaka et al, , 2003. To gain further insight into events downstream of the PARaPKC complex, we searched for genes that are reciprocally regulated by PAR-3 and Lgl.…”

Section: Girdin Gene Expression Is Regulated By Par-3mentioning

confidence: 99%

“…Girdin mRNA expression is regulated by the PAR-3-aPKC complex aPKC binding to PAR-3 is essential for PAR-3 rescue of apical membrane development in PAR-3 kd cells (Horikoshi et al, 2009). To examine whether aPKC also regulates Girdin mRNA expression, we investigated the effect of depleting aPKCλ, an aPKC predominantly expressed in MDCK cells, on Girdin expression.…”

Section: Girdin Gene Expression Is Regulated By Par-3mentioning

confidence: 99%

“…In Drosophila melanogaster, cooperation of PAR-3 (which is known as Bazooka) with aPKC is indispensable for the establishment of apicobasal membrane identities (Bilder et al, 2003;Wodarz et al, 2000Wodarz et al, , 1999. Moreover, genetic manipulation in mammals, including the targeted disruption of PAR-3 in mice, has also revealed the important in vivo role of PAR-3 in tight junction formation, apical membrane development and lumen formation during epithelial morphogenesis (Chen and Macara, 2005;Hirose et al, 2006;Horikoshi et al, 2009;Hurd et al, 2003). PAR-3 interacts with the aPKC-PAR-6 complex to form the tripartite PAR-3-aPKC-PAR-6 complex (Izumi et al, 1998;Joberty et al, 2000;Lin et al, 2000;Suzuki et al, 2001), which is required for aPKC recruitment to cell-cell contacts and for apical domain development (Horikoshi et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, genetic manipulation in mammals, including the targeted disruption of PAR-3 in mice, has also revealed the important in vivo role of PAR-3 in tight junction formation, apical membrane development and lumen formation during epithelial morphogenesis (Chen and Macara, 2005;Hirose et al, 2006;Horikoshi et al, 2009;Hurd et al, 2003). PAR-3 interacts with the aPKC-PAR-6 complex to form the tripartite PAR-3-aPKC-PAR-6 complex (Izumi et al, 1998;Joberty et al, 2000;Lin et al, 2000;Suzuki et al, 2001), which is required for aPKC recruitment to cell-cell contacts and for apical domain development (Horikoshi et al, 2009). In addition, by binding to PAR-3, the LIMK2 and Tiam1 actin cytoskeleton regulatory proteins and the Sec 8 exocyst protein (also known as EXOC4) have been implicated in epithelial cell polarization (Bryant et al, 2010;Macara, 2005, 2006;Zuo et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of epithelial cell polarity by PAR-3 depends on Girdin transcription and Girdin–Gαi3 signaling

Sasaki

Kakuwa

Akimoto

et al. 2015

Journal of Cell Science

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Epithelial apicobasal polarity has fundamental roles in epithelial physiology and morphogenesis. The PAR complex, comprising PAR-3, PAR-6 and aPKC, is involved in determining cell polarity in various biological contexts, including in epithelial cells. However, it is not fully understood how the PAR complex induces apicobasal polarity. In this study, we show that PAR-3 regulates the protein expression of Girdin (GIV/CCDC88A), a guanine nucleotide exchange factor (GEF) for heterotrimeric Gαi subunits, at the transcriptional level by cooperating with the AP-2 transcription factor. In addition, we confirmed that PAR-3 physically interacts with Girdin, and show that Girdin, together with the Gαi3, controls tight junction formation, apical domain development and actin organization downstream of PAR-3. Taken together, our findings suggest that transcriptional upregulation of Girdin and Girdin–Gαi3 signaling play crucial roles in regulating epithelial apicobasal polarity via the PAR complex.

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Section: Girdin Gene Expression Is Regulated By Par-3mentioning

confidence: 99%

Section: Girdin Gene Expression Is Regulated By Par-3mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Regulation of epithelial cell polarity by PAR-3 depends on Girdin transcription and Girdin–Gαi3 signaling

Sasaki

Kakuwa

Akimoto

et al. 2015

Journal of Cell Science

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“…Par-3 interacts with Par-6 and the effector of this complex, aPKC, via distinct domains (27) and thereby controls Par-6 localization and aPKC activation (30,31). Inhibition of Par complex formation in epithelial cells during development results in delayed morphogenesis via perturbed establishment of apical-basal polarity (32,33). In premyelinating SCs, Par-3 additionally interacts with p75 NTR through its PDZ1 binding domain to relocalize this receptor to axon-glial junctions, thereby promoting in vitro myelination (23).…”

Section: ] (E and F)mentioning

confidence: 99%

Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling

Beirowski¹,

Gustin

Armour

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

151

119

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The formation of myelin by Schwann cells (SCs) occurs via a series of orchestrated molecular events. We previously used global expression profiling to examine peripheral nerve myelination and identified the NAD + -dependent deacetylase Sir-two-homolog 2 (Sirt2) as a protein likely to be involved in myelination. Here, we show that Sirt2 expression in SCs is correlated with that of structural myelin components during both developmental myelination and remyelination after nerve injury. Transgenic mice lacking or overexpressing Sirt2 specifically in SCs show delays in myelin formation. In SCs, we found that Sirt2 deacetylates Par-3, a master regulator of cell polarity. The deacetylation of Par-3 by Sirt2 decreases the activity of the polarity complex signaling component aPKC, thereby regulating myelin formation. These results demonstrate that Sirt2 controls an essential polarity pathway in SCs during myelin assembly and provide insights into the association between intracellular metabolism and SC plasticity.neuropathy | sirtuin | acetylation M yelinating Schwann cells (SCs) perform a range of tasks required for correct function of the peripheral nervous system (PNS). In addition to ensuring normal locomotion and sensation and providing trophic support of axons (1), they control regenerative and reparative responses in peripheral nerves (2). These functions are tightly linked to the ability of differentiated SCs to intimately associate with axons and ensheath them with compact myelin. Various pathways in SCs have been identified that are crucial for this process including neuronal growth factors, cell adhesion, and a number of second messenger systems (3). These pathways are interrelated with strict temporal control of key transcription factors, collectively responsible for up-regulation of genes critical for structural assembly of myelin (3, 4).Metabolic derangements contribute to a major class of conditions in which SC function is impaired. For example, numerous studies indicate that nerve regeneration and myelination after injury are impaired in diabetic neuropathy (5-8). Moreover, SC myelination can be altered by changes in nutrition (9, 10). These findings give rise to the idea that abnormal metabolic conditions could lead to aberrant myelination via abnormalities in SC function. We previously identified Sir-two-homolog 2 (Sirt2) in gene expression profiling experiments as a putative myelinationassociated protein on the basis of the similarity of its expression to that of mRNAs encoding structural myelin proteins during periods of myelin formation (11). Sirt2 is a member of the conserved sirtuin family of NAD + -dependent deacetylases that modulate cellular processes in accord with the metabolic state (12, 13). Depending on the cellular context and tissue type, Sirt2 is reported to deacetylate α-tubulin (14, 15), control cell division (16), regulate adipocyte differentiation through FOXO1 (17), and alter gene expression via the deacetylation of histone H4 (18) among other functions.Here, we demonstrate that norm...

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PDZ Domains as Drug Targets

Christensen

Čalyševa

Fernandes

et al. 2019

Advanced Therapeutics

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Protein-protein interactions within protein networks shape the human interactome, which often is promoted by specialized protein interaction modules, such as the postsynaptic density-95 (PSD-95), discs-large, zona occludens 1 (ZO-1) (PDZ) domains. PDZ domains play a role in several cellular functions, from cell-cell communication and polarization, to regulation of protein transport and protein metabolism. PDZ domain proteins are also crucial in the formation and stability of protein complexes, establishing an important bridge between extracellular stimuli detected by transmembrane receptors and intracellular responses. PDZ domains have been suggested as promising drug targets in several diseases, ranging from neurological and oncological disorders to viral infections. In this review, the authors describe structural and genetic aspects of PDZ-containing proteins and discuss the current status of the development of small-molecule and peptide modulators of PDZ domains. An overview of potential new therapeutic interventions in PDZ-mediated protein networks is also provided.

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Interaction between PAR-3 and the aPKC–PAR-6 complex is indispensable for apical domain development of epithelial cells

Cited by 156 publications

References 48 publications

Regulation of epithelial cell polarity by PAR-3 depends on Girdin transcription and Girdin–Gαi3 signaling

Regulation of epithelial cell polarity by PAR-3 depends on Girdin transcription and Girdin–Gαi3 signaling

Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling

PDZ Domains as Drug Targets

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