FRMD4A regulates epithelial polarity by connecting Arf6 activation with the PAR complex

Ikenouchi, Junichi; Umeda, Masato

doi:10.1073/pnas.0908423107

Cited by 81 publications

(95 citation statements)

References 40 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6,7 Its protein sequence has similarity to the highly related proteins 4.1 protein, Ezrin, radixin and moesin, comprising the FERM protein superfamily. 7,8 This superfamily includes ubiquitous components of the cytocortex involved in cell structure, transport and signaling functions.…”

Section: Discussionmentioning

confidence: 99%

“…7,8 This superfamily includes ubiquitous components of the cytocortex involved in cell structure, transport and signaling functions. 6 FERM proteins contain three domains: the FERM domain, a central helical domain and a C-terminal tail domain, which binds F-actin. The FERM domain, located at the N terminus of the majority of FERM-containing proteins 7,8 is responsible for cytoskeleton-membrane cross-linking: it attaches to the membrane by binding specific membrane proteins, whereas the last 34 residues of the C-terminal tail domain bind actin filaments.…”

Section: Discussionmentioning

confidence: 99%

“…8 In epithelial cells, FRMD4A was shown to regulate cell polarity by connecting ARF6 activation with the PAR complex (Par3/Par6/aPKC/ Cdc42), known to function in various cell polarization events. 6,7 Activation of ARF6, a central player in actin cytoskeleton dynamics and membrane trafficking, is spatiotemporally regulated as a downstream signaling pathway of the Par protein complex: 8,9 activation of ARF6 requires activity of guanine nucleotide exchange factors (GEFs), proteins exchanging GDP for GTP. 9 Activation of ARF6 in the process of epithelial polarization is restrictively controlled via Cytohesin family proteins: Cytohesin1 is the GEF for ARF6, stimulating guanine FRMD4 mutation in novel microcephaly syndrome D Fine et al nucleotide exchange of ARF6.…”

Section: Discussionmentioning

confidence: 99%

“…6 FRMD4A binds directly to the coiledcoil domain of cytohesin1, yet has direct interaction also with the Par3 protein: amino acids 565-920 of FRMD4A directly interact with Par3 and are necessary and sufficient for its localization at primordial AJs and TJs. 6 The fact that FRMD4A binds to both Par3 and the ARF6 GEF (cytohesin1) suggests that FRMD4A mediates the interaction between them and that the Par3/FRMD4A/cytohesin1 complex ensures accurate activation of ARF6 protein. 4 In the predicted mutant truncated FRMD4A protein, the coiled-coil region is not affected, but serine-rich regions which are known to interact with the Par3 protein are altered: of amino acids 565-920 of FRMD4A, the predicted mutant protein ends at amino acid 740 with only 716 initial amino acids being of the original protein sequence.…”

Section: Discussionmentioning

confidence: 99%

“…Arf6 has been shown to modulate morphological processes crucial for proper formation of the neuronal circuits in the brain, including regulating cell polarity in neurons, dendrite and axon differentiation, development of dendritic arbor complexity and dendritic spine formation, as well as determining dendritic branching in hippocampal neurons and neurite outgrowth in PC12 cells. 8,9 As seen in molecular processes determining epithelial cell polarity, 6 FRMD4A has an important role in the activation of ARF6 through mediating the interaction between Par3 and the ARF6 GEF. It is thus likely that the neurological phenotype seen in the affected individuals is due to inability of the mutant FRMD4A to mediate such interaction in the absence of part of the domain that is essential for Par3 binding.…”

Section: Discussionmentioning

confidence: 99%

See 4 more Smart Citations

A syndrome of congenital microcephaly, intellectual disability and dysmorphism with a homozygous mutation in FRMD4A

et al. 2014

View full text Add to dashboard Cite

A consanguineous Bedouin Israeli kindred presented with a novel autosomal recessive intellectual disability syndrome of congenital microcephaly, low anterior hairline, bitemporal narrowing, low-set protruding ears, strabismus and tented thick eyebrows with sparse hair in their medial segment. Brain imaging demonstrated various degrees of agenesis of corpus callosum and hypoplasia of the vermis and cerebellum. Genome-wide linkage analysis followed by fine mapping defined a 7.67 Mb disease-associated locus (LOD score 4.99 at θ = 0 for marker D10S1653). Sequencing of the 48 genes within the locus identified a single non-synonymous homozygous duplication frameshift mutation of 13 nucleotides (c.2134_2146dup13) within the coding region of FRMD4A, that was common to all affected individuals and not found in 180 non-related Bedouin controls. Three of 50 remotely related healthy controls of the same tribe were heterozygous for the mutation. FRMD4A, member of the FERM superfamily, is involved in cell structure, transport and signaling. It regulates cell polarity by playing an important role in the activation of ARF6, mediating the interaction between Par3 and the ARF6 guanine nucleotide exchange factor. ARF6 is known to modulate cell polarity in neurons, and regulates dendritic branching in hippocampal neurons and neurite outgrowth. The FRMD4 domain that is essential for determining cell polarity through interaction with Par3 is truncated by the c.2134_2146dup13 mutation. FRMD4A polymorphisms were recently suggested to be a risk factor for Alzheimer's disease. We now show a homozygous frameshift mutation of the same gene in a severe neurologic syndrome with unique dysmorphism.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

A syndrome of congenital microcephaly, intellectual disability and dysmorphism with a homozygous mutation in FRMD4A

et al. 2014

View full text Add to dashboard Cite

show abstract

Cell Adhesion Structures in Epithelial Cells Are Formed in Dynamic and Cooperative Ways

Shigetomi

Ikenouchi

2019

BioEssays

Self Cite

View full text Add to dashboard Cite

There are many morphologically distinct membrane structures with different functions at the surface of epithelial cells. Among these, adherens junctions (AJ) and tight junctions (TJ) are responsible for the mechanical linkage of epithelial cells and epithelial barrier function, respectively. In the process of new cell-cell adhesion formation between two epithelial cells, such as after wounding, AJ form first and then TJ form on the apical side of AJ. This process is very complicated because AJ formation triggers drastic changes in the organization of actin cytoskeleton, the activity of Rho family of small GTPases, and the lipid composition of the plasma membrane, all of which are required for subsequent TJ formation. In this review, the authors focus on the relationship between AJ and TJ as a representative example of specialization of plasma membrane regions and introduce recent findings on how AJ formation promotes the subsequent formation of TJ. Figure 6. Addition of cholesterol restores the formation of TJ in α-catenin KO cells. Time-lapse imaging of α-catenin KO epithelial cells expressing GFP-claudin-3. Cholesterol-saturated MβCD (75 mM) was added to the medium to restore the level of cholesterol in the plasma membrane at time 0. GFP-claudin-3 gradually accumulate at the cell-cell interface and TJ is formed even in the absence of AJ. Scale bar, 20 µm. Adapted with permission. [72]

show abstract

Imaging genomics discovery of a new risk variant for Alzheimer's disease in the postsynaptic SHARPIN gene

Soheili-Nezhad

Jahanshad

Guelfi

et al. 2020

Human Brain Mapping

View full text Add to dashboard Cite

Molecular mechanisms underlying Alzheimer's disease (AD) are difficult to investigate, partly because diagnosis lags behind the insidious pathological processes. Therefore, identifying AD neuroimaging markers and their genetic modifiers may help study early mechanisms of neurodegeneration. We aimed to identify brain regions of the highest vulnerability to AD using a data‐driven search in the AD Neuroimaging Initiative (ADNI, n = 1,100 subjects), and further explored genetic variants affecting this critical brain trait using both ADNI and the younger UK Biobank cohort ( n = 8,428 subjects). Tensor‐Based Morphometry (TBM) and Independent Component Analysis (ICA) identified the limbic system and its interconnecting white‐matter as the most AD‐vulnerable brain feature. Whole‐genome analysis revealed a common variant in SHARPIN that was associated with this imaging feature (rs34173062, p = 2.1 × 10 −10 ). This genetic association was validated in the UK Biobank, where it was correlated with entorhinal cortical thickness bilaterally ( p = .002 left and p = 8.6 × 10 −4 right), and with parental history of AD ( p = 2.3 × 10 −6 ). Our findings suggest that neuroanatomical variation in the limbic system and AD risk are associated with a novel variant in SHARPIN. The role of this postsynaptic density gene product in β1‐integrin adhesion is in line with the amyloid precursor protein (APP) intracellular signaling pathway and the recent genome‐wide evidence.

show abstract

FRMD4A regulates epithelial polarity by connecting Arf6 activation with the PAR complex

Cited by 81 publications

References 40 publications

A syndrome of congenital microcephaly, intellectual disability and dysmorphism with a homozygous mutation in FRMD4A

A syndrome of congenital microcephaly, intellectual disability and dysmorphism with a homozygous mutation in FRMD4A

Cell Adhesion Structures in Epithelial Cells Are Formed in Dynamic and Cooperative Ways

Imaging genomics discovery of a new risk variant for Alzheimer's disease in the postsynaptic SHARPIN gene

Contact Info

Product

Resources

About