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Class IX Myosins: Motorized RhoGAP Signaling Molecules

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Myosins

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1239))

Abstract

Class IX myosins are simultaneously motor and signaling molecules. In addition to myosin class-specific functions of the tail region, they feature unique motor properties. Within their motor region they contain a long insertion with a calmodulin- and a F-actin-binding site. The rate-limiting step in the ATPase cycle is ATP hydrolysis rather than, typical for other myosins, the release of either product. This means that class IX myosins spend a large fraction of their cycle time in the ATP-bound state, which is typically a low F-actin affinity state. Nevertheless, class IX myosins in the ATP-bound state stochastically switch between a low and a high F-actin affinity state. Single motor domains even show characteristics of processive movement towards the plus end of actin filaments. The insertion thereby acts as an actin tether. The motor domain transports as intramolecular cargo a signaling Rho GTPase-activating protein domain located in the tail region. Rho GTPase-activating proteins catalyze the conversion of active GTP-bound Rho to inactive GDP-bound Rho by stimulating GTP hydrolysis. In cells, Rho activity regulates actin cytoskeleton organization and actomyosin II contractility. Thus, class IX myosins regulate cell morphology, cell migration, cell-cell junctions and membrane trafficking. These cellular functions affect embryonic development, adult organ homeostasis and immune responses. Human diseases associated with mutations in the two class IX myosins, Myo9a and Myo9b, have been identified, including hydrocephalus and congenital myasthenic syndrome in connection with Myo9a and autoimmune diseases in connection with Myo9b.

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References

  • Abouhamed M, Grobe K, San IV, Thelen S, Honnert U, Balda MS, Matter K, Bähler M (2009) Myosin IXa regulates epithelial differentiation and its deficiency results in hydrocephalus. Mol Biol Cell 20(24):5074–5085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H (2014) An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteome 96:253–262

    Article  CAS  Google Scholar 

  • Chandhoke SK, Mooseker MS (2012) A role for myosin IXb, a motor-RhoGAP chimera, in epithelial wound healing and tight junction regulation. Mol Biol Cell 23(13):2468–2480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen YQ, Zhang L, Lv XY, Wang HZ (2016) lack of association between myo9b gene polymorphisms and susceptibility to coeliac disease in caucasians: evidence from a meta-analysis. Immunol Investig 45(5):396–405

    Article  CAS  Google Scholar 

  • Chieregatti E, Gärtner A, Stöffler HE, Bähler M (1998) Myr 7 is a novel myosin IX-RhoGAP expressed in rat brain. J Cell Sci 111(Pt 24):3597–3608

    CAS  PubMed  Google Scholar 

  • Daub H, Olsen JV, Bairlein M, Gnad F, Oppermann FS, Körner R, Greff Z, Kéri G, Stemmann O, Mann M (2008) Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell 31(3):438–448

    Article  CAS  PubMed  Google Scholar 

  • Dephoure N, Zhou C, Villén J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP (2008) A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A 105(31):10762–10767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diakonova M, Bokoch G, Swanson JA (2002) Dynamics of cytoskeletal proteins during Fcgamma receptor-mediated phagocytosis in macrophages. Mol Biol Cell 13(2):402–411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elfrink K, Liao W, Pieper U, Oeding SJ, Bähler M (2014) The loop2 insertion of type IX myosin acts as an electrostatic actin tether that permits processive movement. PLoS One 9(1):e84874

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Folci A, Murru L, Vezzoli E, Ponzoni L, Gerosa L, Moretto E, Longo F, Zapata J, Braida D, Pistillo F, Bähler M, Francolini M, Sala M, Bassani S (2016) Myosin IXa binds AMPAR and regulates synaptic structure, LTP, and cognitive function. Front Mol Neurosci 9:1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gnad F, Gunawardena J, Mann M (2011) PHOSIDA 2011: the posttranslational modification database. Nucleic Acids Res 39(Database):D253–D260

    Article  CAS  PubMed  Google Scholar 

  • Graf B, Bähler M, Hilpelä P, Böwe C, Adam T (2000) Functional role for the class IX myosin myr5 in epithelial cell infection by Shigella flexneri. Cell Microbiol 2(6):601–616

    Article  CAS  PubMed  Google Scholar 

  • Handa Y, Durkin CH, Dodding MP, Way M (2013) Vaccinia virus F11 promotes viral spread by acting as a PDZ-containing scaffolding protein to bind myosin-9A and inhibit RhoA signaling. Cell Host Microbe 14(1):51–62

    Article  CAS  PubMed  Google Scholar 

  • Haney MS, Bohlen CJ, Morgens DW, Ousey JA, Barkal AA, Tsui CK, Ego BK, Levin R, Kamber RA, Collins H, Tucker A, Li A, Vorselen D, Labitigan L, Crane E, Boyle E, Jiang L, Chan J, Rincón E, Greenleaf WJ, Li B, Snyder MP, Weissman IL, Theriot JA, Collins SR, Barres BA, Bassik MC (2018) Identification of phagocytosis regulators using magnetic genome-wide CRISPR screens. Nat Genet 50(12):1716–1727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanley PJ, Xu Y, Kronlage M, Grobe K, Schön P, Song J, Sorokin L, Schwab A, Bähler M (2010) Motorized RhoGAP myosin IXb (Myo9b) controls cell shape and motility. Proc Natl Acad Sci U S A 107(27):12145–12150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hegan PS, Chandhoke SK, Barone C, Egan M, Bähler M, Mooseker MS (2016) Mice lacking myosin IXb, an inflammatory bowel disease susceptibility gene, have impaired intestinal barrier function and superficial ulceration in the ileum. Cytoskeleton (Hoboken) 73(4):163–179

    Article  CAS  Google Scholar 

  • Huttlin EL, Jedrychowski MP, Elias JE, Goswami T, Rad R, Beausoleil SA, Villén J, Haas W, Sowa ME, Gygi SP (2010) A tissue-specific atlas of mouse protein phosphorylation and expression. Cell 143(7):1174–1189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inoue A, Saito J, Ikebe R, Ikebe M (2002) Myosin IXb is a single-headed minus-end-directed processive motor. Nat Cell Biol 4(4):302–306

    Article  CAS  PubMed  Google Scholar 

  • Kalhammer G, Bähler M, Schmitz F, Jöckel J, Block C (1997) Ras-binding domains: predicting function versus folding. FEBS Lett 414(3):599–602

    Article  CAS  PubMed  Google Scholar 

  • Kambara T, Ikebe M (2006) A unique ATP hydrolysis mechanism of single-headed processive myosin, myosin IX. J Biol Chem 281(8):4949–4957

    Article  CAS  PubMed  Google Scholar 

  • Kim DG, Jeong YH, McMichael BK, Bähler M, Bodnyk K, Sedlar R, Lee BS (2018) Relationships of bone characteristics in MYO9B deficient femurs. J Mech Behav Biomed Mater 84:99–107

    Article  CAS  PubMed  Google Scholar 

  • Kollmar M, Mühlhausen S (2017) Myosin repertoire expansion coincides with eukaryotic diversification in the Mesoproterozoic era. BMC Evol Biol 17(1):211

    Article  PubMed  PubMed Central  Google Scholar 

  • Kong R, Yi F, Wen P, Liu J, Chen X, Ren J, Li X, Shang Y, Nie Y, Wu K, Fan D, Zhu L, Feng W, Wu JY (2015) Myo9b is a key player in SLIT/ROBO-mediated lung tumor suppression. J Clin Invest 125(12):4407–4420

    Article  PubMed  PubMed Central  Google Scholar 

  • Li P, Yang XK, Wang X, Zhao MQ, Zhang C, Tao SS, Zhao W, Huang Q, Li LJ, Pan HF, Ye DQ (2016) A meta-analysis of the relationship between MYO9B gene polymorphisms and susceptibility to Crohn’s disease and ulcerative colitis. Hum Immunol 77(10):990–996

    Article  CAS  PubMed  Google Scholar 

  • Liao W, Elfrink K, Bähler M (2010) Head of myosin IX binds calmodulin and moves processively toward the plus-end of actin filaments. J Biol Chem 285(32):24933–24942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Z, Xu Y, Zhang X, Song J, Sorokin L, Bähler M (2015) The motorized RhoGAP myosin IXb (Myo9b) in leukocytes regulates experimental autoimmune encephalomyelitis induction and recovery. J Neuroimmunol 282:25–32

    Article  CAS  PubMed  Google Scholar 

  • Lundby A, Secher A, Lage K, Nordsborg NB, Dmytriyev A, Lundby C, Olsen JV (2012) Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues. Nat Commun 3:876

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ma D, Zheng B, Suzuki T, Zhang R, Jiang C, Bai D, Yin W, Yang Z, Zhang X, Hou L, Zhan H, Wen JK (2017) Inhibition of KLF5-Myo9b-RhoA pathway-mediated podosome formation in macrophages ameliorates abdominal aortic aneurysm. Circ Res 120(5):799–815

    Article  CAS  PubMed  Google Scholar 

  • Maddirevula S, Alzahrani F, Al-Owain M, Al Muhaizea MA, Kayyali HR, AlHashem A, Rahbeeni Z, Al-Otaibi M, Alzaidan HI, Balobaid A, El Khashab HY, Bubshait DK, Faden M, Yamani SA, Dabbagh O, Al-Mureikhi M, Jasser AA, Alsaif HS, Alluhaydan I, Seidahmed MZ, Alabbasi BH, Almogarri I, Kurdi W, Akleh H, Qari A, Al Tala SM, Alhomaidi S, Kentab AY, Salih MA, Chedrawi A, Alameer S, Tabarki B, Shamseldin HE, Patel N, Ibrahim N, Abdulwahab F, Samira M, Goljan E, Abouelhoda M, Meyer BF, Hashem M, Shaheen R, AlShahwan S, Alfadhel M, Ben-Omran T, Al-Qattan MM, Monies D, Alkuraya FS (2019) Autozygome and high throughput confirmation of disease genes candidacy. Genet Med 21(3):736–742

    Article  CAS  PubMed  Google Scholar 

  • McMichael BK, Jeong YH, Auerbach JA, Han CM, Sedlar R, Shettigar V, Bähler M, Agarwal S, Kim DG, Lee BS (2017) The RhoGAP Myo9b promotes bone growth by mediating osteoblastic responsiveness to IGF-1. J Bone Miner Res 32(10):2103–2115

    Article  CAS  PubMed  Google Scholar 

  • Moalli F, Ficht X, Germann P, Vladymyrov M, Stolp B, de Vries I, Lyck R, Balmer J, Fiocchi A, Kreutzfeldt M, Merkler D, Iannacone M, Ariga A, Stoffel MH, Sharpe J, Bähler M, Sixt M, Diz-Muñoz A, Stein JV (2018) The Rho regulator Myosin IXb enables nonlymphoid tissue seeding of protective CD8+ T cells. J Exp Med 215(7):1869–1890

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Müller RT, Honnert U, Reinhard J, Bähler M (1997) The rat myosin myr 5 is a GTPase-activating protein for Rho in vivo: essential role of arginine 1695. Mol Biol Cell 8(10):2039–2053

    Article  PubMed  PubMed Central  Google Scholar 

  • Nalavadi V, Nyitrai M, Bertolini C, Adamek N, Geeves MA, Bähler M (2005) Kinetic mechanism of myosin IXB and the contributions of two class IX-specific regions. J Biol Chem 280(47):38957–38968

    Article  CAS  PubMed  Google Scholar 

  • Nijmeijer RM, van Santvoort HC, Zhernakova A, Teller S, Scheiber JA, de Kovel CG, Besselink MG, Visser JT, Lutgendorff F, Bollen TL, Boermeester MA, Rijkers GT, Weiss FU, Mayerle J, Lerch MM, Gooszen HG, Akkermans LM, Wijmenga C, Dutch Pancreatitis Study Group (2013) Association analysis of genetic variants in the myosin IXB gene in acute pancreatitis. PLoS One 8(12):e85870

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nishikawa M, Nishikawa S, Inoue A, Iwane AH, Yanagida T, Ikebe M (2006) A unique mechanism for the processive movement of single-headed myosin-IX. Biochem Biophys Res Commun 343(4):1159–1164

    Article  CAS  PubMed  Google Scholar 

  • Nitta R, Kikkawa M, Okada Y, Hirokawa N (2004) KIF1A alternately uses two loops to bind microtubules. Science 305(5684):678–683

    Article  CAS  PubMed  Google Scholar 

  • O’Connell CB, Mooseker MS (2003) Native Myosin-IXb is a plus-, not a minus-end-directed motor. Nat Cell Biol 5(2):171–172

    Article  PubMed  CAS  Google Scholar 

  • O’Connor E, Töpf A, Müller JS, Cox D, Evangelista T, Colomer J, Abicht A, Senderek J, Hasselmann O, Yaramis A, Laval SH, Lochmüller H (2016) Identification of mutations in the MYO9A gene in patients with congenital myasthenic syndrome. Brain 139(Pt 8):2143–2153

    Article  PubMed  PubMed Central  Google Scholar 

  • O’Connor E, Phan V, Cordts I, Cairns G, Hettwer S, Cox D, Lochmüller H, Roos A (2018) MYO9A deficiency in motor neurons is associated with reduced neuromuscular agrin secretion. Hum Mol Genet 27(8):1434–1446

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Okada Y, Hirokawa N (2000) Mechanism of the single-headed processivity: diffusional anchoring between the K-loop of kinesin and the C terminus of tubulin. Proc Natl Acad Sci U S A 97(2):640–645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okada Y, Higuchi H, Hirokawa N (2003) Processivity of the single-headed kinesin KIF1A through biased binding to tubulin. Nature 424(6948):574–577

    Article  CAS  PubMed  Google Scholar 

  • Omelchenko T, Hall A (2012) Myosin-IXA regulates collective epithelial cell migration by targeting RhoGAP activity to cell-cell junctions. Curr Biol 22(4):278–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Post PL, Bokoch GM, Mooseker MS (1998) Human myosin-IXb is a mechanochemically active motor and a GAP for rho. J Cell Sci 111(Pt 7):941–950

    CAS  PubMed  Google Scholar 

  • Post PL, Tyska MJ, O’Connell CB, Johung K, Hayward A, Mooseker MS (2002) Myosin-IXb is a single-headed and processive motor. J Biol Chem 277(14):11679–11683

    Article  CAS  PubMed  Google Scholar 

  • Reinhard J, Scheel AA, Diekmann D, Hall A, Ruppert C, Bähler M (1995) A novel type of myosin implicated in signalling by rho family GTPases. EMBO J 14(4):697–704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rigbolt KT, Prokhorova TA, Akimov V, Henningsen J, Johansen PT, Kratchmarova I, Kassem M, Mann M, Olsen JV, Blagoev B (2011) System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation. Sci Signal 4(164):rs3

    Article  PubMed  Google Scholar 

  • Saczko-Brack D, Warchol E, Rogez B, Kröss M, Heissler SM, Sellers JR, Batters C, Veigel C (2016) Self-organization of actin networks by a monomeric myosin. Proc Natl Acad Sci U S A 113(52):E8387–E8395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scheffzek K, Ahmadian MR, Wittinghofer A (1998) GTPase-activating proteins: helping hands to complement an active site. Trends Biochem Sci 23(7):257–262

    Article  CAS  PubMed  Google Scholar 

  • Struchholz S, Elfrink K, Pieper U, Kalhammer G, Honnert U, Grützner A, Linke WA, Liao W, Bähler M (2009) Functional role of the extended loop 2 in the myosin 9b head for binding F-actin. J Biol Chem 284(6):3663–3671

    Article  CAS  PubMed  Google Scholar 

  • Thelen S, Abouhamed M, Ciarimboli G, Edemir B, Bähler M (2015) Rho GAP myosin IXa is a regulator of kidney tubule function. Am J Physiol Ren Physiol 309(6):F501–F513

    Article  CAS  Google Scholar 

  • van den Boom F, Düssmann H, Uhlenbrock K, Abouhamed M, Bähler M (2007) The Myosin IXb motor activity targets the myosin IXb RhoGAP domain as cargo to sites of actin polymerization. Mol Biol Cell 18(4):1507–1518

    Article  PubMed  PubMed Central  Google Scholar 

  • Wallace AG, Raduwan H, Carlet J, Soto MC (2018) The RhoGAP HUM-7/Myo9 integrates signals to modulate RHO-1/RhoA during embryonic morphogenesis in Caenorhabditis elegans. Development 145(23):dev168724

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang MJ, Xu XL, Yao GL, Yu Q, Zhu CF, Kong ZJ, Zhao H, Tang LM, Qin XH (2016) MYO9B gene polymorphisms are associated with the risk of inflammatory bowel diseases. Oncotarget 7(37):58862–58875

    Article  PubMed  PubMed Central  Google Scholar 

  • Wirth JA, Jensen KA, Post PL, Bement WM, Mooseker MS (1996) Human myosin-IXb, an unconventional myosin with a chimerin-like rho/rac GTPase-activating protein domain in its tail. J Cell Sci 109(Pt 3):653–661

    CAS  PubMed  Google Scholar 

  • Xie P (2010) A model for processive movement of single-headed myosin-IX. Biophys Chem 151(1–2):71–80

    Article  PubMed  CAS  Google Scholar 

  • Xu Y, Pektor S, Balkow S, Hemkemeyer SA, Liu Z, Grobe K, Hanley PJ, Shen L, Bros M, Schmidt T, Bähler M, Grabbe S (2014) Dendritic cell motility and T cell activation requires regulation of Rho-cofilin signaling by the Rho-GTPase activating protein myosin IXb. J Immunol 192(8):3559–3568

    Article  CAS  PubMed  Google Scholar 

  • Yi F, Kong R, Ren J, Zhu L, Lou J, Wu JY, Feng W (2016) Noncanonical Myo9b-RhoGAP accelerates RhoA GTP hydrolysis by a Dual-Arginine-finger mechanism. J Mol Biol 428(15):3043–3057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yiş U, Becker K, Kurul SH, Uyanik G, Bayram E, Haliloğlu G, Polat Aİ, Ayanoğlu M, Okur D, Tosun AF, Serdaroğlu G, Yilmaz S, Topaloğlu H, Anlar B, Cirak S, Engel AG (2017) Genetic Landscape of congenital myasthenic syndromes from Turkey: Novel mutations and clinical insights. J Child Neurol 32(8):759–765

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhou H, Di Palma S, Preisinger C, Peng M, Polat AN, Heck AJ, Mohammed S (2013) Toward a comprehensive characterization of a human cancer cell phosphoproteome. J Proteome Res 12(1):260–271

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

M.B. acknowledges the support by the “Deutsche Forschungsgemeinschaft” grant BA1354/14-1.

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  1. Institute of Molecular Cell Biology, Westfalian Wilhelms University Münster, Münster, Germany

    Peter J. Hanley, Veith Vollmer & Martin Bähler

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  1. Peter J. Hanley
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  2. Veith Vollmer
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Correspondence to Martin Bähler .

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  1. Department of Physiology & Biophysics, Boston University School of Medicine, Boston, MA, USA

    Lynne M. Coluccio

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Hanley, P.J., Vollmer, V., Bähler, M. (2020). Class IX Myosins: Motorized RhoGAP Signaling Molecules. In: Coluccio, L. (eds) Myosins. Advances in Experimental Medicine and Biology, vol 1239. Springer, Cham. https://doi.org/10.1007/978-3-030-38062-5_16

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