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The intrinsically disordered region of the cytokinetic F-BAR protein Cdc15 performs a unique essential function in maintenance of cytokinetic ring integrity.
Mangione MC, Snider CE, Gould KL
(2019) Mol Biol Cell 30: 2790-2801
MeSH Terms: Cell Cycle Proteins, Cell Division, Cytokinesis, Cytoskeletal Proteins, GTP-Binding Proteins, Protein Domains, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, src Homology Domains
Show Abstract · Added March 3, 2020
Successful separation of two daughter cells (i.e., cytokinesis) is essential for life. Many eukaryotic cells divide using a contractile apparatus called the cytokinetic ring (CR) that associates dynamically with the plasma membrane (PM) and generates force that contributes to PM ingression between daughter cells. In important membrane-CR scaffolds include the paralogous F-BAR proteins Cdc15 and Imp2. Their conserved protein structure consists of the archetypal F-BAR domain linked to an SH3 domain by an intrinsically disordered region (IDR). Functions have been assigned to the F-BAR and SH3 domains. In this study we probed the function of the central IDR. We found that the IDR of Cdc15 is essential for viability and cannot be replaced by that of Imp2, whereas the F-BAR domain of Cdc15 can be swapped with several different F-BAR domains, including that of Imp2. Deleting part of the IDR results in CR defects and abolishes calcineurin phosphatase localization to the CR. Together these results indicate that Cdc15's IDR has a nonredundant essential function that coordinates regulation of CR architecture.
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9 MeSH Terms
Myosin IIA drives membrane bleb retraction.
Taneja N, Burnette DT
(2019) Mol Biol Cell 30: 1051-1059
MeSH Terms: Actins, Animals, Blister, COS Cells, Cell Membrane, Cell Membrane Structures, Cell Movement, Cell Surface Extensions, Chlorocebus aethiops, Cytokinesis, Cytoplasm, Cytoskeletal Proteins, HeLa Cells, Humans, Myosin Type II, Nerve Tissue Proteins, Nonmuscle Myosin Type IIA, Nonmuscle Myosin Type IIB
Show Abstract · Added March 27, 2019
Membrane blebs are specialized cellular protrusions that play diverse roles in processes such as cell division and cell migration. Blebbing can be divided into three distinct phases: bleb nucleation, bleb growth, and bleb retraction. Following nucleation and bleb growth, the actin cortex, comprising actin, cross-linking proteins, and nonmuscle myosin II (MII), begins to reassemble on the membrane. MII then drives the final phase, bleb retraction, which results in reintegration of the bleb into the cellular cortex. There are three MII paralogues with distinct biophysical properties expressed in mammalian cells: MIIA, MIIB, and MIIC. Here we show that MIIA specifically drives bleb retraction during cytokinesis. The motor domain and regulation of the nonhelical tailpiece of MIIA both contribute to its ability to drive bleb retraction. These experiments have also revealed a relationship between faster turnover of MIIA at the cortex and its ability to drive bleb retraction.
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18 MeSH Terms
Epithelial-Mesenchymal Transition Induces Podocalyxin to Promote Extravasation via Ezrin Signaling.
Fröse J, Chen MB, Hebron KE, Reinhardt F, Hajal C, Zijlstra A, Kamm RD, Weinberg RA
(2018) Cell Rep 24: 962-972
MeSH Terms: Animals, Breast Neoplasms, Cell Line, Tumor, Cytoskeletal Proteins, Epithelial-Mesenchymal Transition, Female, Heterografts, Humans, Lung Neoplasms, Male, Mice, Mice, Inbred NOD, Mice, SCID, Pancreatic Neoplasms, Sialoglycoproteins, Signal Transduction
Show Abstract · Added April 10, 2019
The epithelial-mesenchymal transition (EMT) endows carcinoma cells with traits needed to complete many of the steps leading to metastasis formation, but its contributions specifically to the late step of extravasation remain understudied. We find that breast cancer cells that have undergone an EMT extravasate more efficiently from blood vessels both in vitro and in vivo. Analysis of gene expression changes associated with the EMT program led to the identification of an EMT-induced cell-surface protein, podocalyxin (PODXL), as a key mediator of extravasation in mesenchymal breast and pancreatic carcinoma cells. PODXL promotes extravasation through direct interaction of its intracellular domain with the cytoskeletal linker protein ezrin. Ezrin proceeds to establish dorsal cortical polarity, enabling the transition of cancer cells from a non-polarized, rounded cell morphology to an invasive extravasation-competent shape. Hence, the EMT program can directly enhance the efficiency of extravasation and subsequent metastasis formation through a PODXL-ezrin signaling axis.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms
Dorsolateral Striatum Engagement Interferes with Early Discrimination Learning.
Bergstrom HC, Lipkin AM, Lieberman AG, Pinard CR, Gunduz-Cinar O, Brockway ET, Taylor WW, Nonaka M, Bukalo O, Wills TA, Rubio FJ, Li X, Pickens CL, Winder DG, Holmes A
(2018) Cell Rep 23: 2264-2272
MeSH Terms: Adaptation, Physiological, Animals, Choice Behavior, Corpus Striatum, Cytoskeletal Proteins, Discrimination Learning, Light, Male, Mice, Inbred C57BL, Nerve Tissue Proteins
Show Abstract · Added March 26, 2019
In current models, learning the relationship between environmental stimuli and the outcomes of actions involves both stimulus-driven and goal-directed systems, mediated in part by the DLS and DMS, respectively. However, though these models emphasize the importance of the DLS in governing actions after extensive experience has accumulated, there is growing evidence of DLS engagement from the onset of training. Here, we used in vivo photosilencing to reveal that DLS recruitment interferes with early touchscreen discrimination learning. We also show that the direct output pathway of the DLS is preferentially recruited and causally involved in early learning and find that silencing the normal contribution of the DLS produces plasticity-related alterations in a PL-DMS circuit. These data provide further evidence suggesting that the DLS is recruited in the construction of stimulus-elicited actions that ultimately automate behavior and liberate cognitive resources for other demands, but with a cost to performance at the outset of learning.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
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10 MeSH Terms
Cdk1-dependent phosphoinhibition of a formin-F-BAR interaction opposes cytokinetic contractile ring formation.
Willet AH, Bohnert KA, Gould KL
(2018) Mol Biol Cell 29: 713-721
MeSH Terms: Actin Cytoskeleton, Actins, CDC2 Protein Kinase, Cell Cycle Proteins, Cell Division, Cytokinesis, Cytoskeletal Proteins, GTP-Binding Proteins, Phosphorylation, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added March 14, 2018
In , cytokinesis requires the assembly and constriction of an actomyosin-based contractile ring (CR). A single essential formin, Cdc12, localizes to the cell middle upon mitotic onset and nucleates the F-actin of the CR. Cdc12 medial recruitment is mediated in part by its direct binding to the F-BAR scaffold Cdc15. Given that Cdc12 is hyperphosphorylated in M phase, we explored whether Cdc12 phosphoregulation impacts its association with Cdc15 during mitosis. We found that Cdk1, a major mitotic kinase, phosphorylates Cdc12 on six N-terminal residues near the Cdc15-binding site, and phosphorylation on these sites inhibits its interaction with the Cdc15 F-BAR domain. Consistent with this finding, a mutant with all six Cdk1 sites changed to phosphomimetic residues () displays phenotypes similar to , in which the Cdc15-binding motif is disrupted; both show reduced Cdc12 at the CR and delayed CR formation. Together, these results indicate that Cdk1 phosphorylation of formin Cdc12 antagonizes its interaction with Cdc15 and thereby opposes Cdc12's CR localization. These results are consistent with a general role for Cdk1 in inhibiting cytokinesis until chromosome segregation is complete.
© 2018 Willet et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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11 MeSH Terms
The C-terminal region of A-kinase anchor protein 350 (AKAP350A) enables formation of microtubule-nucleation centers and interacts with pericentriolar proteins.
Kolobova E, Roland JT, Lapierre LA, Williams JA, Mason TA, Goldenring JR
(2017) J Biol Chem 292: 20394-20409
MeSH Terms: A Kinase Anchor Proteins, Biomarkers, Cell Cycle Proteins, Cell Line, Centrosome, Cytoskeletal Proteins, Humans, Imaging, Three-Dimensional, Intracellular Signaling Peptides and Proteins, Luminescent Proteins, Microscopy, Electron, Transmission, Microtubule-Associated Proteins, Microtubule-Organizing Center, Models, Molecular, Nerve Tissue Proteins, Peptide Fragments, Phosphoproteins, Protein Interaction Domains and Motifs, Protein Interaction Mapping, Protein Multimerization, Proteomics, RNA Interference, Recombinant Fusion Proteins, Recombinant Proteins, Two-Hybrid System Techniques
Show Abstract · Added April 3, 2018
Microtubules in animal cells assemble (nucleate) from both the centrosome and the cis-Golgi cisternae. A-kinase anchor protein 350 kDa (AKAP350A, also called AKAP450/CG-NAP/AKAP9) is a large scaffolding protein located at both the centrosome and Golgi apparatus. Previous findings have suggested that AKAP350 is important for microtubule dynamics at both locations, but how this scaffolding protein assembles microtubule nucleation machinery is unclear. Here, we found that overexpression of the C-terminal third of AKAP350A, enhanced GFP-AKAP350A(2691-3907), induces the formation of multiple microtubule-nucleation centers (MTNCs). Nevertheless, these induced MTNCs lacked "true" centriole proteins, such as Cep135. Mapping analysis with AKAP350A truncations demonstrated that AKAP350A contains discrete regions responsible for promoting or inhibiting the formation of multiple MTNCs. Moreover, GFP-AKAP350A(2691-3907) recruited several pericentriolar proteins to MTNCs, including γ-tubulin, pericentrin, Cep68, Cep170, and Cdk5RAP2. Proteomic analysis indicated that Cdk5RAP2 and Cep170 both interact with the microtubule nucleation-promoting region of AKAP350A, whereas Cep68 interacts with the distal C-terminal AKAP350A region. Yeast two-hybrid assays established a direct interaction of Cep170 with AKAP350A. Super-resolution and deconvolution microscopy analyses were performed to define the association of AKAP350A with centrosomes, and these studies disclosed that AKAP350A spans the bridge between centrioles, co-localizing with rootletin and Cep68 in the linker region. siRNA-mediated depletion of AKAP350A caused displacement of both Cep68 and Cep170 from the centrosome. These results suggest that AKAP350A acts as a scaffold for factors involved in microtubule nucleation at the centrosome and coordinates the assembly of protein complexes associating with the intercentriolar bridge.
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25 MeSH Terms
Structure of Myo7b/USH1C complex suggests a general PDZ domain binding mode by MyTH4-FERM myosins.
Li J, He Y, Weck ML, Lu Q, Tyska MJ, Zhang M
(2017) Proc Natl Acad Sci U S A 114: E3776-E3785
MeSH Terms: Adaptor Proteins, Signal Transducing, Caco-2 Cells, Cell Cycle Proteins, Cytoskeletal Proteins, Humans, Multiprotein Complexes, Myosin VIIa, Myosins, PDZ Domains, Protein Structure, Quaternary
Show Abstract · Added April 10, 2018
Unconventional myosin 7a (Myo7a), myosin 7b (Myo7b), and myosin 15a (Myo15a) all contain MyTH4-FERM domains (myosin tail homology 4-band 4.1, ezrin, radixin, moesin; MF) in their cargo binding tails and are essential for the growth and function of microvilli and stereocilia. Numerous mutations have been identified in the MyTH4-FERM tandems of these myosins in patients suffering visual and hearing impairment. Although a number of MF domain binding partners have been identified, the molecular basis of interactions with the C-terminal MF domain (CMF) of these myosins remains poorly understood. Here we report the high-resolution crystal structure of Myo7b CMF in complex with the extended PDZ3 domain of USH1C (a.k.a., Harmonin), revealing a previously uncharacterized interaction mode both for MyTH4-FERM tandems and for PDZ domains. We predicted, based on the structure of the Myo7b CMF/USH1C PDZ3 complex, and verified that Myo7a CMF also binds to USH1C PDZ3 using a similar mode. The structure of the Myo7b CMF/USH1C PDZ complex provides mechanistic explanations for >20 deafness-causing mutations in Myo7a CMF. Taken together, these findings suggest that binding to PDZ domains, such as those from USH1C, PDZD7, and Whirlin, is a common property of CMFs of Myo7a, Myo7b, and Myo15a.
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10 MeSH Terms
Trafficking Ion Transporters to the Apical Membrane of Polarized Intestinal Enterocytes.
Engevik AC, Goldenring JR
(2018) Cold Spring Harb Perspect Biol 10:
MeSH Terms: Animals, Cell Membrane, Cell Polarity, Cystic Fibrosis Transmembrane Conductance Regulator, Cytoskeletal Proteins, Enterocytes, Humans, Ion Transport, Malabsorption Syndromes, Membrane Transport Proteins, Microvilli, Mucolipidoses, Myosin Heavy Chains, Myosin Type V, Protein Transport, Sodium-Hydrogen Exchanger 3
Show Abstract · Added April 18, 2017
Epithelial cells lining the gastrointestinal tract require distinct apical and basolateral domains to function properly. Trafficking and insertion of enzymes and transporters into the apical brush border of intestinal epithelial cells is essential for effective digestion and absorption of nutrients. Specific critical ion transporters are delivered to the apical brush border to facilitate fluid and electrolyte uptake. Maintenance of these apical transporters requires both targeted delivery and regulated membrane recycling. Examination of altered apical trafficking in patients with Microvillus Inclusion disease caused by inactivating mutations in MYO5B has led to insights into the regulation of apical trafficking by elements of the apical recycling system. Modeling of MYO5B loss in cell culture and animal models has led to recognition of Rab11a and Rab8a as critical regulators of apical brush border function. All of these studies show the importance of apical membrane trafficking dynamics in maintenance of polarized epithelial cell function.
Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.
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16 MeSH Terms
The LIM protein complex establishes a retinal circuitry of visual adaptation by regulating Pax6 α-enhancer activity.
Kim Y, Lim S, Ha T, Song YH, Sohn YI, Park DJ, Paik SS, Kim-Kaneyama JR, Song MR, Leung A, Levine EM, Kim IB, Goo YS, Lee SH, Kang KH, Kim JW
(2017) Elife 6:
MeSH Terms: Adaptation, Ocular, Animals, Cytoskeletal Proteins, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, LIM Domain Proteins, LIM-Homeodomain Proteins, Mice, Mice, Knockout, PAX6 Transcription Factor, Retina, Transcription Factors
Show Abstract · Added February 14, 2018
The visual responses of vertebrates are sensitive to the overall composition of retinal interneurons including amacrine cells, which tune the activity of the retinal circuitry. The expression of is regulated by multiple cis-DNA elements including the intronic α-enhancer, which is active in GABAergic amacrine cell subsets. Here, we report that the transforming growth factor ß1-induced transcript 1 protein (Tgfb1i1) interacts with the LIM domain transcription factors Lhx3 and Isl1 to inhibit the α-enhancer in the post-natal mouse retina. mice show elevated α-enhancer activity leading to overproduction of Pax6ΔPD isoform that supports the GABAergic amacrine cell fate maintenance. Consequently, the mouse retinas show a sustained light response, which becomes more transient in mice with the auto-stimulation-defective mutation. Together, we show the antagonistic regulation of the α-enhancer activity by Pax6 and the LIM protein complex is necessary for the establishment of an inner retinal circuitry, which controls visual adaptation.
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13 MeSH Terms
Comparative genetic screens in human cells reveal new regulatory mechanisms in WNT signaling.
Lebensohn AM, Dubey R, Neitzel LR, Tacchelly-Benites O, Yang E, Marceau CD, Davis EM, Patel BB, Bahrami-Nejad Z, Travaglini KJ, Ahmed Y, Lee E, Carette JE, Rohatgi R
(2016) Elife 5:
MeSH Terms: Casein Kinase I, Cytoskeletal Proteins, Gene Expression Regulation, Gene Regulatory Networks, Genes, Reporter, Genetic Testing, Haploidy, Humans, Wnt Proteins, Wnt Signaling Pathway
Show Abstract · Added February 13, 2017
The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers of regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted a systematic forward genetic analysis through reporter-based screens in haploid human cells. Comparison of screens for negative, attenuating and positive regulators of WNT signaling, mediators of R-spondin-dependent signaling and suppressors of constitutive signaling induced by loss of the tumor suppressor adenomatous polyposis coli or casein kinase 1α uncovered new regulatory features at most levels of the pathway. These include a requirement for the transcription factor AP-4, a role for the DAX domain of AXIN2 in controlling β-catenin transcriptional activity, a contribution of glycophosphatidylinositol anchor biosynthesis and glypicans to R-spondin-potentiated WNT signaling, and two different mechanisms that regulate signaling when distinct components of the β-catenin destruction complex are lost. The conceptual and methodological framework we describe should enable the comprehensive understanding of other signaling systems.
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10 MeSH Terms