Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Mini Review

MAPRE1 (-associated , RP/EB family, member 1) Jennifer S Tirnauer Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, E1032, Farmington, CT 06030-3101, USA (JST)

Published in Atlas Database: November 2004 Online updated version : http://AtlasGeneticsOncology.org/Genes/MAPRE1ID455ch20q11.html DOI: 10.4267/2042/38147 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity DNA/RNA Other names: EB1 Description HGNC (Hugo): MAPRE1 22 Kb genomic locus, 5 introns. Location : 20q11.1-11.23 Transcription Location () : 32,123,450 - 32,153,886 bp. 2540 bp open reading frame. Protein Description 268 amino acids; 35 kDa; EB1 was cloned in yeast two-hybrid screen as binding partner for the tumor suppressor APC (Adenomatous Polyposis Coli); EB1 is a microtubule plus end tracking protein (+tip). It contains a calponin homology domain and a leucine zipper. Expression EB1 is ubiquitously expressed. Protein levels remain similar throughout the cell cycle. Localisation EB1 targets to the plus ends of when they are polymerizing, producing a "comet tail" pattern.

(Figure 1). The mechanism is treadmilling, in which EB1-GFP fluorescence on polymerizing microtubule plus ends new subunits are continually added at the tip. in a living PtK1 cell. EB1 also shows additional weak binding to the Note microtubule lattice (along the length of the The original name EB1 came from a yeast two hybrid microtubule). EB1 targets to kinetochores moving anti- screen "End Binding 1" is a nickname that was later poleward. This is suspected to be due to binding to applied when the protein was found to target to kinetochore microtubule plus ends rather than the microtubule plus ends. kinetochore itself. Through its carboxyl terminus, EB1 localizes to centrosomes and spindle poles.

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MAPRE1 (Microtubule-associated protein, RP/EB family, member 1) Tirnauer JS

Function binds to the APC C-terminus, so its binding is lost in most truncations. Also lost are other APC binding The primary function identified to date is regulation of partners including the transcription factor beta-catenin. microtubule dynamic instability. Microtubules The role of APC as a tumor suppressor is thought to be dynamically convert between growth (polymerization) through the beta-catenin pathway. Some evidence in and shrinkage (depolymerization). The transition from the mouse suggests that this is true. growth to shrinkage is called catastrophe, while the However, there is increasing evidence that connections conversion from shrinkage to growth is called rescue. between APC and the cytoskeleton are important in cell Microtubules also pause in their polymerization. EB1 migration, which could have an important role in colon reduces these pauses and reduces the frequency of cancer. One Italian FAP family has been reported in catastrophes. EB1 increases the frequency of rescues. which APC is truncated distal to the beta-catenin The net result is more stable, longer microtubules. This binding site but including the EB1 binding site. There effect is predominantly seen during mitosis. is no direct evidence of EB1 mutation in colon cancer, EB1 is important in maintaining the structure of the and a single report found no evidence of somatic mitotic spindle. This is thought to be mediated by its mutations by reverse transcriptase single-strand effects on spindle microtubule dynamic instability. conformational polymorphism (SSCP) analysis in 21 EB1 is important in spindle positioning within the cell. sporadic colorectal cancers and seven colorectal This is thought to be due to its effects on astral adenomas. microtubule dynamic instability. In budding yeast, EB1 also plays a role in positioning the mitotic spindle Meduloblastoma through the bud neck. In this case, it is through Disease microtubule dynamics as well direct binding to a A single report showed that EB1 is transcriptionally protein at the bud tip, creating a physical link between elevated in pediatric meduloblastoma. There is no the microtubule end and the cell cortex. direct evidence of EB1 mutation in meduloblastoma. EB1 plays a role in linking kinetochores to kinetochore microtubules, which is important for stability. It is not known whether it regulates Breakpoints kinetochore microtubule dynamics or end-on Note attachment. None known. EB1 also has an independent role in anchoring microtubule minus ends to centrosomes References Protein-protein interactions: Adenomatous Polyposis Coli (APC) tumor suppressor, polymerized tubulin Su LK, Burrell M, Hill DE, Gyuris J, Brent R, Wiltshire R, Trent (microtubules), p150glued/dynactin, CLIP-170, mDia, J, Vogelstein B, Kinzler KW. APC binds to the novel protein Pin2/TRF1, RhoGEF2 (drosophila), shortstop EB1. Cancer Res. 1995 Jul 15;55(14):2972-7 (drosophila). Renner C, Pfitzenmeier JP, Gerlach K, Held G, Ohnesorge S, Sahin U, Bauer S, Pfreundschuh M. RP1, a new member of Homology the adenomatous polyposis coli-binding EB1-like family, is differentially expressed in activated T cells. J Immunol. 1997 MAPRE2, MAPRE3. Aug 1;159(3):1276-83 Schwartz K, Richards K, Botstein D. BIM1 encodes a Mutations microtubule-binding protein in yeast. Mol Biol Cell. 1997 Note Dec;8(12):2677-91 None known. Berrueta L, Kraeft SK, Tirnauer JS, Schuyler SC, Chen LB, Hill DE, Pellman D, Bierer BE. The adenomatous polyposis coli- binding protein EB1 is associated with cytoplasmic and spindle Implicated in microtubules. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10596-601 Colon cancer Jaïs P, Sabourin JC, Bombled J, Rougier P, Lasser P, Disease Duvillard P, Bénard J, Bressac-de Paillerets B. Absence of somatic alterations of the EB1 gene adenomatous polyposis Truncation of the Adenomatous Polyposis Coli (APC) coli-associated protein in human sporadic colorectal cancers. protein is seen in Familial Adenomatous Polyposis Br J Cancer. 1998 Nov;78(10):1356-60 (FAP) as well as most sporadic colon cancers. EB1

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Morrison EE, Wardleworth BN, Askham JM, Markham AF, Rogers SL, Rogers GC, Sharp DJ, Vale RD. Drosophila EB1 is Meredith DM. EB1, a protein which interacts with the APC important for proper assembly, dynamics, and positioning of tumour suppressor, is associated with the microtubule the mitotic spindle. J Cell Biol. 2002 Sep 2;158(5):873-84 cytoskeleton throughout the cell cycle. Oncogene. 1998 Dec 31;17(26):3471-7 Tirnauer JS, Canman JC, Salmon ED, Mitchison TJ. EB1 targets to kinetochores with attached, polymerizing Muhua L, Adames NR, Murphy MD, Shields CR, Cooper JA. A microtubules. Mol Biol Cell. 2002 Dec;13(12):4308-16 cytokinesis checkpoint requiring the yeast homologue of an APC-binding protein. Nature. 1998 Jun 4;393(6684):487-91 Tirnauer JS, Grego S, Salmon ED, Mitchison TJ. EB1- microtubule interactions in Xenopus egg extracts: role of EB1 Berrueta L, Tirnauer JS, Schuyler SC, Pellman D, Bierer BE. in microtubule stabilization and mechanisms of targeting to The APC-associated protein EB1 associates with components microtubules. Mol Biol Cell. 2002 Oct;13(10):3614-26 of the dynactin complex and cytoplasmic dynein intermediate chain. Curr Biol. 1999 Apr 22;9(8):425-8 Bu W, Su LK. Characterization of functional domains of human EB1 family . J Biol Chem. 2003 Dec 12;278(50):49721- Juwana JP, Henderikx P, Mischo A, Wadle A, Fadle N, 31 Gerlach K, Arends JW, Hoogenboom H, Pfreundschuh M, Renner C. EB/RP gene family encodes tubulin binding Goodson HV, Skube SB, Stalder R, Valetti C, Kreis TE, proteins. Int J Cancer. 1999 Apr 12;81(2):275-84 Morrison EE, Schroer TA. CLIP-170 interacts with dynactin complex and the APC-binding protein EB1 by different Tirnauer JS, O'Toole E, Berrueta L, Bierer BE, Pellman D. mechanisms. Cell Motil Cytoskeleton. 2003 Jul;55(3):156-73 Yeast Bim1p promotes the G1-specific dynamics of microtubules. J Cell Biol. 1999 May 31;145(5):993-1007 Hayashi I, Ikura M. Crystal structure of the amino-terminal microtubule-binding domain of end-binding protein 1 (EB1). J Askham JM, Moncur P, Markham AF, Morrison EE. Regulation Biol Chem. 2003 Sep 19;278(38):36430-4 and function of the interaction between the APC tumour suppressor protein and EB1. Oncogene. 2000 Apr Ligon LA, Shelly SS, Tokito M, Holzbaur EL. The microtubule 6;19(15):1950-8 plus-end proteins EB1 and dynactin have differential effects on microtubule polymerization. Mol Biol Cell. 2003 Korinek WS, Copeland MJ, Chaudhuri A, Chant J. Molecular Apr;14(4):1405-17 linkage underlying microtubule orientation toward cortical sites in yeast. Science. 2000 Mar 24;287(5461):2257-9 Mathur J, Mathur N, Kernebeck B, Srinivas BP, Hülskamp M. A novel localization pattern for an EB1-like protein links Lee L, Tirnauer JS, Li J, Schuyler SC, Liu JY, Pellman D. microtubule dynamics to endomembrane organization. Curr Positioning of the mitotic spindle by a cortical-microtubule Biol. 2003 Nov 11;13(22):1991-7 capture mechanism. Science. 2000 Mar 24;287(5461):2260-2 Subramanian A, Prokop A, Yamamoto M, Sugimura K, Uemura Mimori-Kiyosue Y, Shiina N, Tsukita S. The dynamic behavior T, Betschinger J, Knoblich JA, Volk T. Shortstop recruits of the APC-binding protein EB1 on the distal ends of EB1/APC1 and promotes microtubule assembly at the muscle- microtubules. Curr Biol. 2000 Jul 13;10(14):865-8 tendon junction. Curr Biol. 2003 Jul 1;13(13):1086-95 Tirnauer JS, Bierer BE. EB1 proteins regulate microtubule Louie RK, Bahmanyar S, Siemers KA, Votin V, Chang P, dynamics, cell polarity, and chromosome stability. J Cell Biol. Stearns T, Nelson WJ, Barth AI. Adenomatous polyposis coli 2000 May 15;149(4):761-6 and EB1 localize in close proximity of the mother centriole and EB1 is a functional component of centrosomes. J Cell Sci. Nakamura M, Zhou XZ, Lu KP. Critical role for the EB1 and 2004 Mar 1;117(Pt 7):1117-28 APC interaction in the regulation of microtubule polymerization. Curr Biol. 2001 Jul 10;11(13):1062-7 Rogers SL, Wiedemann U, Häcker U, Turck C, Vale RD. Drosophila RhoGEF2 associates with microtubule plus ends in Su LK, Qi Y. Characterization of human MAPRE and an EB1-dependent manner. Curr Biol. 2004 Oct their proteins. Genomics. 2001 Jan 15;71(2):142-9 26;14(20):1827-33 Askham JM, Vaughan KT, Goodson HV, Morrison EE. Wen Y, Eng CH, Schmoranzer J, Cabrera-Poch N, Morris EJ, Evidence that an interaction between EB1 and p150(Glued) is Chen M, Wallar BJ, Alberts AS, Gundersen GG. EB1 and APC required for the formation and maintenance of a radial bind to mDia to stabilize microtubules downstream of Rho and microtubule array anchored at the centrosome. Mol Biol Cell. promote cell migration. Nat Cell Biol. 2004 Sep;6(9):820-30 2002 Oct;13(10):3627-45 Barth AI, Siemers KA, Nelson WJ. Dissecting interactions This article should be referenced as such: between EB1, microtubules and APC in cortical clusters at the Tirnauer JS. MAPRE1 (Microtubule-associated protein, plasma membrane. J Cell Sci. 2002 Apr 15;115(Pt 8):1583-90 RP/EB family, member 1). Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):3-5.

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