Abstract
MICALs (for Molecule Interacting with CasL) form a recently discovered family of evolutionary conserved signal transduction proteins. They contain multiple well-conserved domains known for interactions with the cytoskeleton, cytoskeletal adaptor proteins, and other signaling proteins. In addition to their ability to bind other proteins, MICALs contain a large NADPH-dependent flavoprotein monooxygenase enzymatic domain. Although MICALs have already been implicated in a variety of cellular processes, their function during axonal pathfinding in the Drosophila neuromuscular system has been best characterized. During the establishment of neuromuscular connectivity in the fruit fly, MICAL binds the axon guidance receptor Plexin A and transduces semaphorin-1a-mediated repulsive axon guidance. Intriguingly, mutagenesis and pharmacological inhibitor studies suggest a role for MICAL flavoenzyme redox functions in semaphorin/plexin-mediated axonal pathfinding events. This review summarizes our current understanding of MICALs, with an emphasis on their role in semaphorin signaling
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Tessier-Lavigne M, Goodman CS. The molecular biology of axon guidance. Science 1996; 274(5290):1123–33.
Dickson BJ. Molecular mechanisms of axon guidance. Science 2002; 298(5600):1959–64.
Huber AB, Kolodkin AL, Ginty DD et al. Signaling at the growth cone: Ligand-receptor complexes and the control of axon growth and guidance. Annu Rev Neurosci 2003; 26:509–63.
Raper JA. Semaphorins and their receptors in vertebrates and invertebrates. Curr Opin Neurobiol 2000; 10:88–94.
Fiore R, Puschel AW. The function of semaphorins during nervous system development. Front Biosci 2003; 8:s484–99.
Casazza A, Fazzari P, Tamagnone L. Semaphorin signals in cell adhesion and cell migration: Functional role and molecular mechanisms. THIS BOOK 2006.
Neufeld G, Lange T, Varshavsky A et al. Semaphorin signaling in vascular and tumor biology. THIS BOOK 2006.
Potiron V, Nassare P, Roche J et al. Semaphorin signaling in the immune system. THIS BOOK 2006.
Toyofuku T, Kikutani H. Semaphorin signaling during cardiac development. THIS BOOK 2006.
Bechara A, Falk J, Moret F et al. Modulation of Semaphorin signaling by Ig super family cell adhesion molecules. THIS BOOK 2006.
Kruger RP, Aurandt J, Guan KL. Semaphorins command cells to move. Nat Rev Mol Cell Biol 2005; 6(10):789–800.
Pasterkamp RJ, Kolodkin AL. Semaphorin junction: Making tracks toward neural connectivity. Curr Opin Neurobiol 2003; 13:79–89.
Ahmed A, Eickholt B. Intracellular kinases in Semaphorin signaling. THIS BOOK 2006.
Castellani V, Rougon P. Control of semaphorin signaling. Curr Opin Neurobiol 2002; 12:532–541.
Puschel AW. GTPases in semaphorin signaling. THIS BOOK 2006.
Schmidt EF, Strittmatter SM. The CRMP family of proteins and their role in Sema3A signaling. THIS BOOK 2006.
Shim S, Ming Gl. Signaling of secreted semaphorins in growth cone steering. THIS BOOK 2006.
Suzuki T, Nakamoto T, Ogawa S et al. MICAL, a novel CasL interacting molecule, associates with vimentin. J Biol Chem 2002; 277:14933–14941.
Terman JR, Mao T, Pasterkamp RJ et al. MICALs, a family of conserved flavoprotein oxidoreductases, function in plexin-mediated axonal repulsion. Cell 2002; 109:887–900.
Terai T, Nishimura N, Kanda I et al. JRAB/MICAL-L2 is a junctional Rab13-binding protein mediating the endocytic recycling of occludin. Mol Biol Cell 2006; 17(5):2465–2475.
Weide T, Teuber J, Bayer M et al. MICAL-1 isoform, novel rab1 interacting proteins. Biochem Biophys Res Commun 2003; 306:79–86.
Pasterkamp RJ, Dai H, Terman JR et al. MICAL flavoprotein monooxygenases: Expression during neural development and following spinal cord injuries in the rat. Mol Cell. Neurosci 2006; 31:52–69.
Cohen RI, Rottkamp DM, Maric D et al. A role for semaphorins and neuropilins in oligodendrocyte guidance. J Neurochem 2003; 85:1262–78.
Goldberg JL, Vargas ME, Wang JT et al. An oligodendrocyte lineage-specific semaphorin, Sema5A, inhibits axon growth by retinal ganglion cells. J Neurosci 2004; 24(21):4989–99.
Moreau-Fauvarque C, Kumanogoh A, Camand E et al. inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion. J Neurosci 2003; 8;23(27):9229–39.
Ricard D, Stankoff B, Bagnard D et al. Differential expression of collapsin response mediator proteins (CRMP/ULIP) in subsets of oligodendrocytes in the postnatal rodent brain. Mol Cell Neurosci 2000; 16(4):324–37.
Ricard D, Rogemond V, Charrier E et al. Isolation and expression pattern of human Unc-33-like phosphoprotein 6/collapsin response mediator protein 5 (Ulip6/CRMP5): Coexistence with Ulip2/CRMP2 in Sema3a-sensitive oligodendrocytes. J Neurosci 2001; 21:7203–7214.
Spassky N, de Castro F, Le Bras B et al. Directional guidance of oligodendroglial migration by class 3 semaphorins and netrin-1. J Neurosci 2002; 22:5992–6004.
Giraudon P, Vincent P, Vuaillat C et al. Semaphorin CD100 from activated T lymphocytes induces process extension collapse in oligodendrocytes and death of immature neural cells. J Immunol 2004; 172(2):1246–55.
Pasterkamp RJ, Verhaagen J. Semaphorins in axon regeneration: Developmental guidance molecules gone wrong? Royal Soc Phil Trans B 2006, (in press).
Winberg ML, Noordermeer JN, Tamagnone L et al. Plexin A is a neuronal semaphorin receptor that controls axon guidance. Cell 1998; 95:903–16.
Yu HH, Araj HH, Ralls SA et al. The transmembrane Semaphorin Sema I is required in Drosophila for embryonic motor and CNS axon guidance. Neuron 1998; 20(2):207–20.
Winberg ML, Tamagnone L, Bai J et al. The transmembrane protein Off-track associates with Plexins and functions downstream of Semaphorin signaling during axon guidance. Neuron 2001; 32:53–62.
Ayoob JC, Yu HH, Terman JR et al. The Drosophila receptor guanylyl cyclase Gyc76C is required for semaphorin-1a-plexin A-mediated axonal repulsion. J Neurosci 2004; 24(30):6639–49.
Song H, Ming G, He Z et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 1998; 281(5382):1515–8.
Toyofuku T, Yoshida J, Sugimoto T et al. FARP2 triggers signals for Sema3A-mediated axonal repulsion. Nat Neurosci 2005; 8(12):1712–9.
Hu H, Marton TF, Goodman CS. Plexin B mediates axon guidance in Drosophila by simultaneously inhibiting active Rac and enhancing RhoA signaling. Neuron 2001; 32:39–51.
Bashaw GJ. Semaphorin signaling unplugged: A Nervy AKAP cAMP(s) out on Plexin. Neuron 2004; 42:363–366.
Terman JR, Kolodkin AL. Nervy links protein kinase a to plexin-mediated semaphorin repulsion. Science 2004; 303(5661):1204–7.
Driessens MHE, Hu H, Nobes CD et al. Plexin B semaphorin receptors interact directly with active Rac and regulate the actin cytoskeleton by activating Rho. Curr Biol 2001; 11:339–344.
Feliciello A, Gottesman ME, Avvedimento EV. The biological functions of A-kinase anchor proteins. J Mol Biol 2001; 308(2):99–114.
Ayoob JC, Terman JR, Kolodkin AL. Drosophila Plexin B is a Sema-2a receptor required for axon guidance. Development 2006; 133, (in press).
Kawakami A, Kitsukawa T, Takagi S et al. Developmentally regulated expression of a cell surface protein, neuropilin, in the mouse nervous system. J Neurobiol 1996; 29(1):1–17.
Murakami Y, Suto F, Shimizu M et al. Differential expression of plexin-A subfamily members in the mouse nervous system. Dev Dyn 2001; 220(3):246–58.
Suto F, Murakami Y, Nakamura F et al. Identification and characterization of a novel mouse plexin, plexin-A4. Mech Dev 2003; 120(3):385–96.
Abe I, Kashiwagi K, Noguchi H. Antioxidative galloyl esters as enzyme inhibitors of p-hydroxybenzoate hydroxylase. FEBS Lett 2000; 483:131–134.
Abe I, Seki T, Noguchi H. Potent and selective inhibition of squalene epoxidase by synthetic galloyl esters. Biochem Biophys Res Commun 2000; 270:137–140.
Schmidt EF, Togashi H, Strittmatter SM. Characterization of a multi-molecular signaling complex that mediates Sema3A signaling. Soc Neurosci Abstracts 2004.
Deo RC, Schmidt EF, Elhabazi A et al. Structural bases for CRMP function in plexin-dependent semaphorin3A signaling. EMBO J 2004; 23(1):9–22.
Togashi H, Schmidt EF, Strittmatter SM. RanBPM contributes to Semaphorin3A signaling through Plexin-A receptors. J Neurosci 2006; 26(18):4961–4969.
O’Neill GM, Fashena SJ, Golemis EA. Integrin signaling: A new Cas(t) of characters enters the stage. Trends Cell Biol 2000; 10:111–119.
Yi J, Kloeker S, Jensen CC et al. Members of the Zyxin family of LIM proteins interact with members of the p130Cas family of signal transducers. J Biol Chem 2002; 277:9580–9589.
Barberis D, Artigiani S, Casazza A et al. Plexin signaling hampers integrin-based adhesion, leading to Rho-kinase independent cell rounding, and inhibiting lamellipodia extension and cell motility. FASEB J 2004; 18:592–604.
Serini G, Valdembri D, Zanivan S et al. Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 2003; 424(6947):391–7.
Oinuma I, Katoh H, Negishi M. Molecular dissection of the semaphorin 4D receptor plexin-B1-stimulated R-Ras GTPase-activating protein activity and neurite remodeling in hippocampal neurons. J Neurosci 2004; 24(50):11473–80.
Negishi M, Oinuma I, Katoh H. R-ras as a key player for signaling pathway of plexins. Mol Neurobiol 2005; 32(3):217–22.
Kamiguchi K, Tachibana K, Iwata S et al. Cas-L is required for beta 1 integrin-mediated costimulation in human T cells. J Immunol 1999; 163:563–568.
Foisner R, Wiche G. Intermediate filament-associated proteins. Curr Opin Cell Biol 1991; 3(1):75–81.
Hirokawa N, Hisanaga S, Shiomura Y. MAP2 is a component of crossbridges between microtubules and neurofilaments in the neuronal cytoskeleton: Quick-freeze, deep-etch immunoelectron microscopy and reconstitution studies. J Neurosci 1988; 8(8):2769–79.
Fischer J, Weide T, Barnekow A. The MICAL proteins and rab1: A possible link to the cytoskeleton. Biochem Biophys Res Commun 2005; 328:415–423.
Seabra MC, Coudrier E. Rab GTPases and myosin motors in organelle motility. Traffic 2004; 5(6):393–9.
Murshid A, Presley JF. ER-to-Golgi transport and cytoskeletal interactions in animal cells. Cell Mol Life Sci 2004; 61(2):133–45.
Finkel T. Oxygen radicals and signaling. Curr Opin Cell Biol 1998; 10:248–253.
Kamata H, Honda S, Maeda S et al. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 2005; 120(5):649–61.
Dalle-Donne I, Rossi R, Milzani A et al. The actin cytoskeleton response to oxidants: From small heat shock protein phosphorylation to changes in the redox state of actin itself. Free Radic Biol Med 2001; 31(12):1624–32.
Dalle-Donne I, Rossi R, Giustarini D et al. Actin carbonylation: From a simple marker of protein oxidation to relevant signs of severe functional impairment. Free Radic Biol Med 2001; 31:1075–83.
Milzani A, Dalle-Donne I, Colombo R. Prolonged oxidative stress on actin. Arch Biochem Biophys 1997; 339(2):267–74.
Gimona M, Djinovic-Carugo K, Kranewitter WJ et al. Functional plasticity of CH domains. FEBS Lett 2002; 513:98–106.
Bach I. The LIM domain: Regulation by association. Mech Dev 2000; 91(1-2):5
Kadrmas JL, Beckerle MC. The LIM domain: From the cytoskeleton to the nucleus. Nat Rev Mol Cell Biol 2004; 5:920–31.
Nadella M, Bianchet MA, Gabelli SB et al. Structure and activity of the axon guidance protein MICAL. Proc Natl Acad Sci USA 2005; 102(46):16830–5.
Siebold C, Berrow N, Walter TS et al. High-resolution structure of the catalytic region of MICAL, a multi-domain flavoenzyme-signaling molecule. Proc Natl Acad Sci USA 2005; 102:16836–16841.
Massey V. Activation of molecular oxygen by flavins and flavoproteins. J Biol Chem 1994; 269(36):22459–62.
Massey V. Introduction: Flavoprotein structure and mechanism. FASEB J 1995; 9(7):473–5.
Wierenga RK, de Jong RJ, Kalk KH et al. Crystal structure of p-hydroxybenzoate hydroxylase. J Mol Biol 1979; 131(1):55–73.
Ghisla S, Massey V. Mechanisms of flavoprotein-catalyzed reactions. Eur J Biochem 1989; 181(1):1–17.
Otterbein LR, Graceffa P, Dominguez R. The crystal structure of uncomplexed actin in the ADP state. Science 2001; 293(5530):708–11.
Finkel T. Redox-dependent signal transduction. FEBS Lett 2000; 476:52–54.
Kamata H, Hirata H. Redox regulation of cellular signaling. Cell Signal 1999; 11:1–14.
Lo YYC, Cruz TF. Involvement of reactive oxygen species in cytokine and growth factor induction of c-fos expression in chondrocytes. J Biol Chem 1995; 270:11727–11730.
Sundaresan M, Yu ZX, Ferrans VJ et al. Requirement for generation of H2O2 for platelet derived growth factor signal transduction. Science 1995; 270:296–299.
Svegliati S, Cancello R, Sambo P et al. Platelet-derived growth factor and reactive oxygen species (ROS) regulate Ras protein levels in primary human fibroblasts via ERK1/2. Amplification of ROS and Ras in systemic sclerosis fibroblasts. J Biol Chem 2005; 280:36474–82.
Rhee SG. Redox signaling: Hydrogen peroxide as intracellular messenger. Exp Mol Med 1999; 31:53–59.
Rhee SG, Bae YS, Lee SR et al. Hydrogen peroxide: A key messenger that modulates protein phosphorylation through cysteine oxidation. Sci STKE 2000; 53:PE1.
Guay J, Lambert H, Gingras-Breton G et al. Regulation of actin filament dynamics by p38 map kinase-mediated phosphorylation of heat shock protein 27. J Cell Sci 1997; 110(Pt 3):357–68.
Ahn SG, Thiele DJ. Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress. Genes Dev 2003; 17(4):516–28.
Kheradmand F, Werner E, Tremble P et al. Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change. Science 1998; 280:898–902.
Moldovan L, Irani K, Moldovan NI et al. The actin cytoskeleton reorganization induced by Rac1 requires the production of superoxide. Antioxid Redox Signal 1999; 1:29–43.
Nimnual AS, Taylor LJ, Bar-Sagi D. Redox-dependent downregulation of Rho by Rac. Nat Cell Biol 2003; 5:236–241.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 Landes Bioscience and Springer Science+Business Media
About this chapter
Cite this chapter
Kolk, S.M., Pasterkamp, R.J. (2007). MICAL Flavoprotein Monooxygenases: Structure, Function and Role in Semaphorin Signaling. In: Pasterkamp, R.J. (eds) Semaphorins: Receptor and Intracellular Signaling Mechanisms. Advances in Experimental Medicine and Biology, vol 600. Springer, New York, NY. https://doi.org/10.1007/978-0-387-70956-7_4
Download citation
DOI: https://doi.org/10.1007/978-0-387-70956-7_4
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-387-70955-0
Online ISBN: 978-0-387-70956-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)