Shank2 Binds to aPKC and Controls Tight Junction Formation with Rap1 Signaling during Establishment of Epithelial Cell Polarity

Sasaki, Kazunori; Kojitani, Noriko; Hirose, Hiroko; Yoshihama, Yohei; Suzuki, Haruo; Shimada, Miho; Takayanagi, Atsushi; Yamashita, Akio; Nakaya, Muneo; Hirano, Hisashi; Takahashi, Hidehisa; Ohno, Shigeo

doi:10.1016/j.celrep.2020.02.088

Cited by 19 publications

(14 citation statements)

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“…Par complex‐mediated TJ formation may also require the Cdc42 GEF FARP2 [91] and the Rho/Cdc42 GEF Ect2 [92,93], although Ect2 has also been shown to function in a different context [94,95]. In addition, the scaffolding protein SHANK2 has recently been shown to control TJ formation by linking the Par complex to Rap1 signaling [96]. Together, this indicates that the Par complex is critical for the coordination of Rho GTPase signaling during TJ assembly, yet the underlying mechanisms are still poorly understood.…”

Section: Formation and Regulation Of The Par Complexmentioning

confidence: 99%

New insights into the organization and regulation of the apical polarity network in mammalian epithelial cells

et al. 2021

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Cell polarity is a fundamental property of most animal cells and is critical during development and for most cell and tissue functions. Epithelial cells are organized into apical and basolateral compartments, and this intrinsic cellular asymmetry is essential for all functions that are carried out by epithelial tissue. The establishment of a polarized epithelial phenotype is orchestrated by major rearrangements of the cell cytoskeleton, polarized membrane trafficking, the formation and maturation of epithelial cell junctions, cell signaling pathways, and the generation of cortical phospholipid asymmetry. These processes need to be coordinated precisely in time and space and integrated with physical and chemical signals from the environment, failure of which leads to severe developmental disorders and various human diseases. At the heart of this regulatory network are the evolutionarily conserved polarity modules Par, Crumbs, and Scribble, whose components engage in complex cooperative and antagonistic interactions to compartmentalize and functionalize the epithelial cell cortex and to control the spatiotemporal activity of downstream polarity effectors. In this review, we will discuss recent insights into the organization and regulation of the mammalian Par and Crumbs modules and outline a hypothetical framework of how these proteins orchestrate epithelial polarity development, HIPPO signaling, and actomyosin activity at the apical–lateral border.

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Section: Formation and Regulation Of The Par Complexmentioning

confidence: 99%

New insights into the organization and regulation of the apical polarity network in mammalian epithelial cells

et al. 2021

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“…Hence, LPHN2 may promote FA turnover by locally funneling Rap1-GTP towards SHANK rather than talin. Interestingly, Rap1-GTP-bound SHANK2 was recently reported to support TJ formation in epithelial cells (Sasaki et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

“…Since, in cultured ECs, LPHN2 stimulates the activation of Rap1 ( Fig. 1 E ), which promotes TJ formation ( Sasaki et al, 2020 ), LPHN2-elicited Rap1 GTP loading may simultaneously hamper the assembly of FAs and support the developing of TJs. In addition, the recruitment of the mechanosensitive adaptor protein ZO-1 at TJs ( Spadaro et al, 2017 ) was recently described to be under the control of forces regulated by ECM stiffness ( Haas et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

“…FLRT2-activated LPHN2 triggers a canonical heterotrimeric G-protein α subunit (Gα)/adenylate cyclase (AC)/cAMP pathway that in turn, likely via the guanine nucleotide exchange factor EPAC, activates the small GTPase Rap1, which is a well-known regulator of cell-to-ECM adhesions ( Coló et al, 2012 ; Lagarrigue et al, 2016 ). Furthermore, Rap1 promotes the formation of TJs ( Sasaki et al, 2020 ), which in ECs are crucial for the control of vascular permeability. Hence, LPHN2 activation of Rap1 may act both to inhibit the formation of FAs and to promote the assembly of TJs, which increase EC barrier function.…”

Section: Resultsmentioning

confidence: 99%

“…Hence, LPHN2 activation of Rap1 may act both to inhibit the formation of FAs and to promote the assembly of TJs, which increase EC barrier function. LPHN2 also binds the central PDZ domain of SHANK adaptor protein that in turn, through its N-terminal SPN domain, binds Rap1-GTP, suppressing talin-mediated integrin activation and FA development ( Lilja et al, 2017 ) and promoting the assembly of TJs ( Sasaki et al, 2020 ). Therefore, LPHN2 may favor the turnover of FAs and the formation of TJs by funneling Rap1-GTP toward SHANK.…”

Section: Resultsmentioning

confidence: 99%

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LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion

Camillo¹,

Facchinello

Villari³

et al. 2021

Journal of Cell Biology

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Dynamic modulation of endothelial cell-to-cell and cell–to–extracellular matrix (ECM) adhesion is essential for blood vessel patterning and functioning. Yet the molecular mechanisms involved in this process have not been completely deciphered. We identify the adhesion G protein–coupled receptor (ADGR) Latrophilin 2 (LPHN2) as a novel determinant of endothelial cell (EC) adhesion and barrier function. In cultured ECs, endogenous LPHN2 localizes at ECM contacts, signals through cAMP/Rap1, and inhibits focal adhesion (FA) formation and nuclear localization of YAP/TAZ transcriptional regulators, while promoting tight junction (TJ) assembly. ECs also express an endogenous LPHN2 ligand, fibronectin leucine-rich transmembrane 2 (FLRT2), that prevents ECM-elicited EC behaviors in an LPHN2-dependent manner. Vascular ECs of lphn2a knock-out zebrafish embryos become abnormally stretched, display a hyperactive YAP/TAZ pathway, and lack proper intercellular TJs. Consistently, blood vessels are hyperpermeable, and intravascularly injected cancer cells extravasate more easily in lphn2a null animals. Thus, LPHN2 ligands, such as FLRT2, may be therapeutically exploited to interfere with cancer metastatic dissemination.

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Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male Mice

et al. 2022

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Mutations of the postsynaptic scaffold protein Shank2 lead to autism spectrum disorders (ASD). These patients frequently suffer from higher fracture risk. Here, we investigated whether Shank2 directly regulates bone mass. We show that Shank2 is expressed in bone and that Shank2 levels are increased during osteoblastogenesis. Knockdown of Shank2 by siRNA targeting the encoding regions for PDZ and SAM domain inhibits osteoblastogenesis of primary murine calvarial osteoblasts. Shank2 knockout mice (Shank2 À/À ) have a decreased bone mass due to reduced osteoblastogenesis and bone formation, whereas bone resorption remains unaffected. Induced pluripotent stem cells (iPSCs)-derived osteoblasts from a loss-of-function Shank2 mutation in a patient showed a significantly reduced osteoblast differentiation potential. Moreover, silencing of known Shank2 interacting proteins revealed that a majority of them promote osteoblast differentiation. From this we conclude that Shank2 and interacting proteins known from the central nervous system are decisive regulators in osteoblast differentiation.

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Shank2 Binds to aPKC and Controls Tight Junction Formation with Rap1 Signaling during Establishment of Epithelial Cell Polarity

Cited by 19 publications

References 93 publications

New insights into the organization and regulation of the apical polarity network in mammalian epithelial cells

New insights into the organization and regulation of the apical polarity network in mammalian epithelial cells

LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion

Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male Mice

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