Conformational plasticity of JRAB/MICAL-L2 provides “law and order” in collective cell migration

Sakane, Ayuko; Yoshizawa, Shin; Nishimura, Masaomi; Tsuchiya, Yuko; Matsushita, Natsuki; Miyake, Kazuhisa; Horikawa, Kazuki; Imoto, Issei; Mizuguchi, Chiharu; Saito, Hiroyuki; Ueno, Takato; Matsushita, Sachi; Haga, Hisashi; Deguchi, Shinji; Mizuguchi, Kenji; Yokota, Hideo; Sasaki, Takuya

doi:10.1091/mbc.e16-05-0332

Cited by 25 publications

(51 citation statements)

References 55 publications

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“…In addition, RAB8 was shown to organize cell adhesion in conjunction with RAB13 by transporting adhesion molecules, in cultured epithelial cells (Sakane et al, 2012). Moreover, the closely RAB8-related RAB13 organizes the collective cell migration of these non-neuronal cells in wounding assays in an ordered manner (Sakane et al, 2016), analogous to our findings with erratic DBN-deficient astrocytes in glial scars in vivo and during live imaging experiments.…”

Section: Cellular Trafficking By Rab8 Tubular Endosomessupporting

confidence: 83%

Drebrin mediates scar formation and astrocyte reactivity during brain injury by inducing RAB8 tubular endosomes

Schiweck

Murk

Ledderose

et al. 2020

Preprint

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The brain of mammals lacks a significant ability to regenerate neurons and is thus particularly vulnerable. To protect the brain from injury and disease, damage control by astrocytes through astrogliosis and scar formation is vital. Here, we show that brain injury triggers an ad hoc upregulation of the actin-binding protein Drebrin (DBN) in astrocytes, which is essential for the formation and maintenance of glial scars in vivo. In turn, DBN loss leads to defective glial scar formation and excessive neurodegeneration following mild brain injuries. At the cellular level, DBN switches actin homeostasis from ARP2/3-dependent arrays to microtubule-compatible scaffolds and facilitates the formation of RAB8-positive membrane tubules. This injury-specific RAB8 membrane compartment serves as hub for the trafficking of surface proteins involved in astrogliosis and adhesive responses, such as β1integrin. Our work identifies DBN as pathology-specific actin regulator, and establishes DBNdependent membrane trafficking as crucial mechanism in protecting the brain from escalating damage following traumatic injuries. MAINThe brain of higher mammals is vulnerable to traumatic injury and disease, but largely lacks the capacity to regenerate neurons and rarely regains function in damaged areas (Barker et al., 2018). This makes the containment of local pathological incidents critical to avoid the propagation of inflammation and neurodegeneration into the uninjured brain parenchyma.Astrocytes are key players in protection of CNS tissue via a defense mechanism known as reactive astrogliosis. This process is associated with comprehensive changes in astrocyte morphology and function (Schiweck et al., 2018). Reactive astrocytes develop hypertrophies of soma and protrusions, while cells in proximity to large lesion sites polarize and extend particularly long processes. Dense arrays of such 'palisades' and hypertrophic astrocytes constitute glial scars, which enclose as physical barriers inflammatory cues and extravasating leucocytes, and limit the spread of damage (Faulkner et al., 2004;Frik et al., 2018). Glial scars are anatomically well described, but the molecular details controlling astrocyte reactivity are still poorly understood.In the context of astrogliosis and scar formation, we studied drebrin (DBN), a cytoskeletal regulator, which stabilizes actin filaments by sidewise binding and by competing off other actin binding proteins (Grintsevich et al., 2010;Mikati et al., 2013). It is widely expressed, but has mainly been studied in neurons (Aoki et al., 2005). In cultured astrocytes, DBN has been described to maintain connexin 43 at the plasma membrane (Butkevich et al., 2004).Functional coupling of astrocytes into networks through gap junctions is essential to modulate neuronal transmission (He et al., 2020;Pannasch and Rouach, 2013). A deficit in DBN would therefore be expected to cause profound phenotypes in vivo. However, mouse models with acute or chronic DBN loss indicate non-essential functions of this actin binding protein d...

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Section: Cellular Trafficking By Rab8 Tubular Endosomessupporting

confidence: 83%

Drebrin mediates scar formation and astrocyte reactivity during brain injury by inducing RAB8 tubular endosomes

Schiweck

Murk

Ledderose

et al. 2020

Preprint

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“…However, the CTD and FMO domains do not interact 140 . A molecular mechanism of the inhibition of FMO activity by CTD or LIM-CTD domains is still unknown, but may involve large conformational changes affecting global MICAL structure, as reported for MICAL-L2/JARB 132 . MICALs have also been proposed to bind themselves or other proteins with DUF3585 domains, opening the door to new regulatory mechanisms based on the formation of homo- or heteromeric complexes 103 .…”

Section: Micalmentioning

confidence: 98%

“…Another interacting partner of MICAL-L1 is collapsin response mediator protein 2 (CRMP2), providing a connection between endosomes and the microtubule cytoskeleton 131 . While MICAL-L1 is mostly associated with endosomal recycling, MICAL-L2 (also known as “Junctional Rab13-binding”, JRAB) has been described as a major regulatory protein in the coordination of collective cell migration 132 . MICAL-L2/JRAB is recruited to cell-cell junctions and cell periphery via interactions with small GTPases like Rab13 133–137 , actin-binding protein (ABP) like actinin-4 138 or nucleotide exchange factors like DENND2B 139 .…”

Section: Micalmentioning

confidence: 99%

Regulated methionine oxidation by monooxygenases

Manta

Gladyshev

2017

Free Radical Biology and Medicine

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Protein function can be regulated via post-translational modifications by numerous enzymatic and non-enzymatic mechanisms, including oxidation of cysteine and methionine residues. Redox-dependent regulatory mechanisms have been identified for nearly every cellular process, but the major paradigm has been that cellular components are oxidized (damaged) by reactive oxygen species (ROS) in a relatively unspecific way, and then reduced (repaired) by designated reductases. While this scheme may work with cysteine, it cannot be ascribed to other residues, such as methionine, whose reaction with ROS is too slow to be biologically relevant. However, methionine is clearly oxidized in vivo and enzymes for its stereoselective reduction are present in all three domains of life. Here, we revisit the chemistry and biology of methionine oxidation, with emphasis on its generation by enzymes from the monooxygenase family. Particular attention is placed on MICALs, a recently discovered family of proteins that harbor an unusual flavin-monooxygenase domain with an NADPH-dependent methionine sulfoxidase activity. Based on the structural and kinetic information we provide a rational framework to explain MICAL mechanism, inhibition, and regulation. Methionine residues that are targeted by MICALs are reduced back by methionine sulfoxide reductases, suggesting that reversible methionine oxidation may be a general mechanism analogous to the regulation by phosphorylation by kinases/phosphatases. The identification of new enzymes that catalyze the oxidation of methionine will open a new area of research at the forefront of redox signaling.

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“…Cell contractility was evaluated using a modified version of a deformable silicone substrate technique (Sakane et al, 2016;Yokoyama et al, 2016). Silicone substrates were prepared as follows: parts A and B of CY 52-276 (Dow Corning Toray, Komatsu, Japan) were mixed at a weight ratio of 1.1:1.…”

Section: Cell Contraction Assaymentioning

confidence: 99%

Vinexin family (SORBS) proteins play different roles in stiffness-sensing and contractile force generation

Ichikawa

Kita

Matsui

et al. 2017

Journal of Cell Science

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Vinexin, c-Cbl associated protein (CAP) and Arg-binding protein 2 (ArgBP2) constitute an adaptor protein family called the vinexin (SORBS) family that is targeted to focal adhesions (FAs). Although numerous studies have focused on each of the SORBS proteins and partially elucidated their involvement in mechanotransduction, a comparative analysis of their function has not been well addressed. Here, we established mouse embryonic fibroblasts that individually expressed SORBS proteins and analysed their functions in an identical cell context. Both vinexin-α and CAP co-localized with vinculin at FAs and promoted the appearance of vinculin-rich FAs, whereas ArgBP2 co-localized with α-actinin at the proximal end of FAs and punctate structures on actin stress fibers (SFs), and induced paxillin-rich FAs. Furthermore, both vinexin-α and CAP contributed to extracellular matrix stiffness-dependent vinculin behaviors, while ArgBP2 stabilized α-actinin on SFs and enhanced intracellular contractile forces. These results demonstrate the differential roles of SORBS proteins in mechanotransduction.

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Conformational plasticity of JRAB/MICAL-L2 provides “law and order” in collective cell migration

Abstract: A multidisciplinary approach reveals key insights into the principles of collective cell migration, which is involved in fundamental biological processes. The conformational plasticity of a single molecule, JRAB/MICAL-L2, provides “law and order” in collective cell migration.

Cited by 25 publications

References 55 publications

Drebrin mediates scar formation and astrocyte reactivity during brain injury by inducing RAB8 tubular endosomes

Drebrin mediates scar formation and astrocyte reactivity during brain injury by inducing RAB8 tubular endosomes

Regulated methionine oxidation by monooxygenases

Vinexin family (SORBS) proteins play different roles in stiffness-sensing and contractile force generation

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