Rab13 Small G Protein and Junctional Rab13-binding Protein (JRAB) Orchestrate Actin Cytoskeletal Organization during Epithelial Junctional Development

Sakane, Ayuko; Abdallah, Ahmed Alamir Mahmoud; Nakano, Kiyoshi; Honda, Kazufumi; Ikeda, Wataru; Nishikawa, Yumiko; Matsumoto, Machiko; Matsushita, Natsuki; Kitamura, Toshio; Sasaki, Takuya

doi:10.1074/jbc.m112.383653

Cited by 46 publications

(82 citation statements)

References 41 publications

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“…CH domains are classified into three types, and MICAL and MICAL-L proteins possess a type-2 CH domain similar to that found in proteins such as smoothelin and microtubule-associated RP/EB (end binding proteins) (38). Type-2 CH domains do not possess the ability to bind directly to F-actin, but can assist type-1 CH domain-containing proteins in binding actin.The CH domains ofMICAL1 and MICAL-L2 were unable to bind to F-actin (65,76). Similar to other type-2 CH domain-containing proteins, MICALs contain a conserved phosphatidylinositol-(4,5)-bisphosphate (PIP2) binding site, and PIP2 has been implicated in F-actin regulation (15,86).…”

Section: Ch Domainmentioning

confidence: 94%

“…MICAL-L2 is recruited to cell-cell junctions through its binding partner and an actin binding protein, Actinin-4 (50). Apart from binding to Actinin-4, MICAL-L2 also binds to actinin-1 (65). Actinins localize to stress fibers, cellular protrusions, and cell adhesion sites, and are capable of rearranging the actin cytoskeleton through their F-actin crosslinking activity (55).…”

Section: Mical-l Proteins In Actin Remodelingmentioning

confidence: 99%

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MICAL-Family Proteins: Complex Regulators of the Actin Cytoskeleton

Giridharan

Caplan²

2014

Antioxidants & Redox Signaling

101

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Significance: The molecules interacting with CasL (MICAL) family members participate in a multitude of activities, including axonal growth cone repulsion, membrane trafficking, apoptosis, and bristle development in flies. An interesting feature of MICAL proteins is the presence of an N-terminal flavo-mono-oxygenase domain. This mono-oxygenase domain generates redox potential with which MICALs can either oxidize proteins or produce reactive oxygen species (ROS). Actin is one such protein that is affected by MICAL function, leading to dramatic cytoskeletal rearrangements. This review describes the MICAL-family members, and discusses their mechanisms of actin-binding and regulation of actin cytoskeleton organization. Recent Advances: Recent studies show that MICALs directly induce oxidation of actin molecules, leading to actin depolymerization. ROS production by MICALs also causes oxidation of collapsin response mediator protein-2, a microtubule assembly promoter, which subsequently undergoes phosphorylation. Critical Issues: MICAL proteins oxidize proteins through two mechanisms: either directly by oxidizing methionine residues or indirectly via the production of ROS. It remains unclear whether MICAL proteins employ both mechanisms or whether the activity of MICALfamily proteins might vary with different substrates. Future Directions: The identification of additional substrates oxidized by MICAL will shed new light on MICAL protein function. Additional directions include expanding studies toward the MICAL-like homologs that lack flavin adenine dinucleotide domains and oxidation activity.

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Section: Ch Domainmentioning

confidence: 94%

Section: Mical-l Proteins In Actin Remodelingmentioning

confidence: 99%

MICAL-Family Proteins: Complex Regulators of the Actin Cytoskeleton

Giridharan

Caplan²

2014

Antioxidants & Redox Signaling

101

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“…Consistently, high levels of actinin-4 are associated with decreased cell motility (78,79). However, upon activation of Rab13, MICAL-L2 binds actinin-4 and suppresses its cross-linking activity and thereby weakening cell-cell adhesion (80).…”

Section: Cell Migration and Scatteringmentioning

confidence: 85%

Regulation of Cancer Cell Behavior by the Small GTPase Rab13

Ioannou

McPherson

2016

Journal of Biological Chemistry

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The members of the Rab family of GTPases are master regulators of cellular membrane trafficking. With ϳ70 members in humans, Rabs have been implicated in all steps of membrane trafficking ranging from vesicle formation and transport to vesicle docking/tethering and fusion. Vesicle trafficking controls the localization and levels of a myriad of proteins, thus regulating cellular functions including proliferation, metabolism, cellcell adhesion, and cell migration. It is therefore not surprising that impairment of Rab pathways is associated with diseases including cancer. In this review, we highlight evidence supporting the role of Rab13 as a potent driver of cancer progression.The members of the Rab (Ras-related in brain) family of proteins are master regulators of vesicle trafficking. They are evolutionarily conserved with ϳ70 members in humans, and each Rab is localized predominantly to a specific intracellular organelle or vesicle (1). Rabs have been implicated in every step of vesicle trafficking including the formation of cargo-laden membrane vesicles and tubules, transport of these carriers on the cytoskeleton, tethering and docking of the carriers at the target membrane, and finally membrane fusion and delivery of cargo. Not surprisingly, functional impairment of Rab pathways is associated with diseases including immunodeficiencies, neurological disorders, and cancer (2). One such Rab, Rab13, controls cellular functions that are often altered in cancer, and Rab13 is now recognized as an important driver of cancer progression. Here, we discuss the importance of Rab13 in the physiology of cancer with a focus on Rab13 trafficking pathways contributing to tumorigenicity. The Biology of Rab13As for all small GTPases, Rab13 cycles between an active, GTP-bound state and an inactive, GDP-bound state. Activation of Rab13 is mediated by DENND2B and DENND1C/connecdenn 3, guanine nucleotide exchange factors (GEFs) 2 that interact with GDP-bound Rab13 and facilitate the exchange of GDP for GTP (3-5). These proteins each bear a differentially expressed in normal and neoplastic cells (DENN) domain, an evolutionarily ancient protein module that encodes GEF activity for a large number of Rab GTPases (6 -8). Rab13 is inactivated by the GTPase-activating protein (GAP) Akt substrate 160 (AS160)/TBC1D4, which enhances the ability of Rab13 to hydrolyze GTP (3-5). In its active form, Rab13 binds to several effectors including MICAL-L1, MICAL-L2, and PKA (9, 10). Rab13, which is ubiquitously expressed, is thought to have diverged from its closest homologue Rab8, early in the vertebrate lineage (11). Similar to Rab8, Rab13 has been implicated in both biosynthetic and endosomal recycling pathways. Rab13 is found at the trans-Golgi network, on recycling endosomes, on late endosomes, and at the plasma membrane (12-14). Disruption of Rab13 function inhibits the delivery of cargo that reaches the plasma membrane via endosomes from either the biosynthetic or the endocytic recycling pathways. Thus, Rab13 is thought to control membrane t...

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“…MICAL-like proteins have been implicated so far in the endocytic pathway (Abou-Zeid et al, 2011;Bahl et al, 2016;Cai et al, 2014;Giridharan and Caplan, 2014;Rahajeng et al, 2010Rahajeng et al, , 2012Reinecke et al, 2015;Sharma et al, 2010Sharma et al, , 2009Terai et al, 2006), exocytosis , phagosomal maturation (Dumas et al, 2015), synaptic development (Nahm et al, 2016), neurite outgrowth (Kobayashi et al, 2014a,b;Kobayashi and Fukuda, 2013), cell division (Reinecke et al, 2015), cell shape (Kanda et al, 2008;Sakane et al, 2012Sakane et al, , 2013, cell junction formation Sakane et al, 2012;Yamamura et al, 2008), cell migration (Sakane et al, 2016) and cancer development (Ioannou et al, 2015;Zhu et al, 2015). As MICAL-like proteins lack the N-terminal monooxygenase domain involved in F-actin oxidation and disassembly, we will essentially focus this Commentary on MICAL proteins.…”

Section: Introductionmentioning

confidence: 99%

Emerging roles of MICAL family proteins – from actin oxidation to membrane trafficking during cytokinesis

Frémont

Romet-Lemonne

Houdusse

et al. 2017

Journal of Cell Science

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Cytokinetic abscission is the terminal step of cell division, leading to the physical separation of the two daughter cells. The exact mechanism mediating the final scission of the intercellular bridge connecting the dividing cells is not fully understood, but requires the local constriction of endosomal sorting complex required for transport (ESCRT)-III-dependent helices, as well as remodelling of lipids and the cytoskeleton at the site of abscission. In particular, microtubules and actin filaments must be locally disassembled for successful abscission. However, the mechanism that actively removes actin during abscission is poorly understood. In this Commentary, we will focus on the latest findings regarding the emerging role of the MICAL family of oxidoreductases in F-actin disassembly and describe how Rab GTPases regulate their enzymatic activity. We will also discuss the recently reported role of MICAL1 in controlling F-actin clearance in the ESCRT-III-mediated step of cytokinetic abscission. In addition, we will highlight how two other members of the MICAL family (MICAL3 and MICAL-L1) contribute to cytokinesis by regulating membrane trafficking. Taken together, these findings establish the MICAL family as a key regulator of actin cytoskeleton dynamics and membrane trafficking during cell division.

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Rab13 Small G Protein and Junctional Rab13-binding Protein (JRAB) Orchestrate Actin Cytoskeletal Organization during Epithelial Junctional Development

Cited by 46 publications

References 41 publications

MICAL-Family Proteins: Complex Regulators of the Actin Cytoskeleton

MICAL-Family Proteins: Complex Regulators of the Actin Cytoskeleton

Regulation of Cancer Cell Behavior by the Small GTPase Rab13

Emerging roles of MICAL family proteins – from actin oxidation to membrane trafficking during cytokinesis

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