MICAL Flavoprotein Monooxygenases: Structure, Function and Role in Semaphorin Signaling

Kolk, Sharon M.; Pasterkamp, R. Jeroen

doi:10.1007/978-0-387-70956-7_4

Cited by 26 publications

(19 citation statements)

References 87 publications

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“…In addition, given that Drosophila MICAL does not destabilize actin by acting as a sequestering or capping protein, and that it decreases the rate and extent of actin polymerization (reviewed by Hung and Terman, 2011), the in vitro studies by Hung and coworkers suggest that Drosophila MICAL acts directly on actin through ROS production (Hung et al, 2010). However, until that study it had not been determined whether ROS are actually generated by MICAL proteins in cells (reviewed by Kolk and Pasterkamp, 2007).…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of actin microfilaments by human MICAL proteins

Giridharan

Rohn

Naslavsky

et al. 2012

Journal of Cell Science

124

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SummaryThe Drosophila melanogaster MICAL protein is essential for the neuronal growth cone machinery that functions through plexin-and semaphorin-mediated axonal signaling. Drosophila MICAL is also involved in regulating myofilament organization and synaptic structures, and serves as an actin disassembly factor downstream of plexin-mediated axonal repulsion. In mammalian cells there are three known isoforms, MICAL1, MICAL2 and MICAL3, as well as the MICAL-like proteins MICAL-L1 and MICAL-L2, but little is known of their function, and information comes almost exclusively from neural cells. In this study we show that in non-neural cells human MICALs are required for normal actin organization, and all three MICALs regulate actin stress fibers. Moreover, we provide evidence that the generation of reactive oxygen species by MICAL proteins is crucial for their actin-regulatory function. However, although MICAL1 is auto-inhibited by its C-terminal coiled-coil region, MICAL2 remains constitutively active and affects stress fibers. These data suggest differential but complementary roles for MICAL1 and MICAL2 in actin microfilament regulation.

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Section: Discussionmentioning

confidence: 99%

Differential regulation of actin microfilaments by human MICAL proteins

Giridharan

Rohn

Naslavsky

et al. 2012

Journal of Cell Science

124

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“…On the basis of the body of current knowledge on MICALs, several hypotheses on its mode of action have been made (Figure 2, [7,9,13]). According to a first hypothesis, MICAL may simply act as a scaffold protein.…”

Section: Discovery and Hypotheses On Mical Functionmentioning

confidence: 99%

“…The scaffold model would explain how MICAL may interfere with CasL [1,8,13] or CRMP [16,24] functions by sequestering them. In support of a scaffold role is the finding that MICAL1 modulates apoptosis by binding NDR1/2 (nuclear Dbf2-related) kinases, through its part spanning from the LIM domain to the C -terminus [42].…”

Section: Discovery and Hypotheses On Mical Functionmentioning

confidence: 99%

MICAL, the Flavoenzyme Participating in Cytoskeleton Dynamics

Vanoni

Vitali

Zucchini

2013

IJMS

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MICAL (from the Molecule Interacting with CasL) indicates a family of recently discovered cytosolic, multidomain proteins, which uniquely couple an N-terminal FAD-containing monooxygenase-like domain to typical calponine homology, LIM and coiled-coil protein-interaction modules. Genetic and cell biology approaches have demonstrated an essential role of the catalytic activity of the monooxygenase-like domain in transducing the signal initiated by semaphorins interaction with their plexin receptors, which results in local actin cytoskeleton disassembly as part of fundamental processes that include differentiation, migration and cell-cell contacts in neuronal and non-neuronal cell types. This review focuses on the structure-function relations of the MICAL monooxygenase-like domain as they are emerging from the available in vitro studies on mouse, human and Drosophila MICAL forms that demonstrated a NADPH-dependent actin depolymerizing activity of MICAL. With Drosophila MICAL forms, actin depolymerization was demonstrated to be associated to conversion of Met44 to methionine sulfone through a postulated hydroxylating reaction. Arguments supporting the concept that MICAL effect on F-actin may be reversible will be discussed.

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“…Based on the structural homology between the FAD domains and other flavoprotein mono-oxygenases, three different mechanisms were proposed to explain how MICALs might impact cytoskeletal reorganization (37,83). The mechanisms include (i) production of reactive oxygen species (ROS), (ii) oxidation of downstream signaling molecules, or (iii) causing direct oxidation and destabilization of actin filaments.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

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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MICAL Flavoprotein Monooxygenases: Structure, Function and Role in Semaphorin Signaling

Cited by 26 publications

References 87 publications

Differential regulation of actin microfilaments by human MICAL proteins

Differential regulation of actin microfilaments by human MICAL proteins

MICAL, the Flavoenzyme Participating in Cytoskeleton Dynamics

MICAL-Family Proteins: Complex Regulators of the Actin Cytoskeleton

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