Alternative titles; symbols
HGNC Approved Gene Symbol: MAPRE1
Cytogenetic location: 20q11.21 Genomic coordinates (GRCh38): 20:32,819,777-32,850,405 (from NCBI)
MAPRE1 is a regulator of microtubule (MT) dynamics that localizes at both the growing plus ends of MTs and the centrosome. It is involved in a variety of cellular processes, including establishment and maintenance of cell polarity, search and capture of chromosomes during mitosis, and positioning of the mitotic spindle during asymmetric cell division (Sun et al., 2008).
EB1 is a 30- to 35-kD protein that was isolated in a yeast 2-hybrid screen by its binding to the C-terminal domain of APC (611731) (Su et al., 1995), a domain that is deleted in the majority of familial and sporadic forms of colon carcinoma.
By genomic sequence analysis, Su and Qi (2001) showed that there are most likely 3 MAPRE genes: MAPRE1, which encodes EB1, MAPRE2 (605789), which encodes RP1 and the EB2 fragment, and MAPRE3 (605788), which encodes EBF3 and the fragment RP3.
Berrueta et al. (1998) undertook a systematic study of EB1 subcellular localization during cell cycle, using both biochemical and immunofluorescence techniques. Using monoclonal antibodies specific for EB1, they demonstrated that EB1 decorated part of the microtubule cytoskeleton during interphase, with pronounced staining of the centrosome. During cell division, EB1 localized to the mitotic apparatus. This microtubule localization was abolished in the presence of the microtubule-destabilizing drug nocodazole; upon drug removal, the microtubule distribution of EB1 was recovered and EB1 fluorescence concentrated at the microtubule-organizing center. These results suggested that EB1 is associated with the microtubule network and may be involved in microtubule polymerization and spindle function. Associating with the mitotic apparatus, EB1 may play a physiologic role connecting APC to cell division, coordinating the control of normal growth and differentiation processes in the colonic epithelium.
Tirnauer and Bierer (2000) reviewed the biology of EB1 family proteins. They noted that EB1 is a microtubule end-binding protein and that EB1 coimmunoprecipitates the dynactin components p150(GLUED) (DCTN1; 601143), p50/dynamitin (DCTN2; 607376), and the intermediate chain of dynein (see DNCI2; 603331) from lymphocytes and epithelial cells (Berrueta et al., 1999).
By yeast 2-hybrid analysis of a HeLa cell cDNA library and pull-down assays using recombinant proteins, Sun et al. (2008) showed that the C-terminal tail of EB1 interacted specifically with the catalytic domain of Aurora kinase B (AURKB; 604970). The proteins colocalized on the central spindle in anaphase and in the midbody during cytokinesis in simian kidney cells, and endogenous EB1 and AURKB coimmunoprecipitated from HeLa cells. EB1 overexpression enhanced AURKB kinase activity, and knockdown of EB1 with small interfering RNA impaired AURKB activity. EB1 protected AURKB from dephosphorylation/inactivation by protein phosphatase-2A (PP2A; see 176915) by blocking binding of PP2A to AURKB. Sun et al. (2008) concluded that EB1 stimulates AURKB activity by antagonizing its dephosphorylation/inactivation by PP2A.
Using various binding assays in human cells, Jiang et al. (2009) showed that TIP150 (MTUS2; 619358) bound EB1 through its EB-binding domains. TIP150 and EB1 colocalized at the plus-end of MTs. TIP150 also directly bound MCAK (KIF2C; 604538). MCAK localization to the plus end of MTs depended on its interaction with TIP150, and this interaction required both N and C termini of MCAK and was disrupted by AURKB-mediated phosphorylation of MCAK. Based on knockdown analyses and pull-down assays, the authors proposed that EB1, TIP150, and MCAK proteins associate at MT tips cooperatively and function in a ternary complex with hierarchical interaction. They found that TIP150 bound EB1 and localized at MT plus ends, then facilitated loading of MCAK onto MT plus ends through physical association, thereby orchestrating the dynamics at the plus end of MTs.
Using U2OS human osteosarcoma cells, Tanenbaum et al. (2011) identified KIF18B (614570) as an essential component of a microtubule-depolymerizing complex containing MCAK and EB1. KIF18B interacted independently with MCAK and a subset of EB1 at microtubule plus ends. All 3 proteins, in addition to KIF18B motor activity, were required for efficient plus-end microtubule depolymerization. Knockdown of either KIF18B or MCAK reduced the localization of the other protein at microtubule plus ends and reduced microtubule depolymerization. Disruption of the MCAK-KIF18B interaction by mutation of the interacting domains, or phosphorylation of MCAK by the microtubule-polymerizing agents Aurora A (AURKA; 603072) or Aurora B, similarly blocked microtubule depolymerization. Use of a KIF5B (602809)/KIF18B chimera revealed that the major role of KIF18B motor domain in this process was to provide plus end-directed movement along microtubules. Tanenbaum et al. (2011) hypothesized that KIF18B, released into the cytoplasm upon mitotic nuclear envelope breakdown, is recruited to microtubule plus ends through interaction with EB1 and MCAK. The motor activity of KIF18B directs the complex to the tip of microtubules, and the depolymerizing activity of the complex is modulated by Aurora A and Aurora B.
Ward et al. (2013) showed that human TIP150 formed a tetramer via its C-terminal coiled-coil domain, and tetrameric TIP150 interacted with EB1 to form a hexameric complex with a stoichiometry of 4:2 for MT plus-end tracking. TIP150-EB1 interaction was required for mitotic progression, as perturbation of the interaction prevented chromosome alignment and delayed anaphase onset. Interaction between TIP150 and EBI was dynamic and was regulated by EB1 acetylation at lys220, which perturbed its interaction with TIP150. Perturbation of the TIP150-EB1 interaction altered accurate attachment of spindle MTs to kinetochore and activated the spindle assembly checkpoint during mitosis.
Su and Qi (2001) determined that MAPRE1, like MAPRE2 and MAPRE3, contains 7 exons. However, the coding region of MAPRE1 spans more than 22 kb due to its long introns.
Using FISH, Su et al. (1995) mapped the MAPRE1 gene to chromosome 20q11.2. Su and Qi (2001) confirmed this localization by identifying MAPRE1 in a genomic clone from chromosome 20q11.1-q11.23.
Berrueta, L., Kraeft, S.-K., Tirnauer, J. S., Schuyler, S. C., Chen, L. B., Hill, D. E., Pellman, D., Bierer, B. E. The adenomatous polyposis coli-binding protein EB1 is associated with cytoplasmic and spindle microtubules. Proc. Nat. Acad. Sci. 95: 10596-10601, 1998. [PubMed: 9724749] [Full Text: https://doi.org/10.1073/pnas.95.18.10596]
Berrueta, L., Tirnauer, J. S., Schuyler, S. C., Pellman, D., Bierer, B. E. The APC-associated protein EB1 associates with components of the dynactin complex and cytoplasmic dynein intermediate chain. Curr. Biol. 9: 425-428, 1999. [PubMed: 10226031] [Full Text: https://doi.org/10.1016/s0960-9822(99)80190-0]
Jiang, K., Wang, J., Liu, J., Ward, T., Wordeman, L., Davidson, A., Wang, F, Yao, X. TIP150 interacts with and targets MCAK at the microtubule plus ends. EMBO Rep. 10: 857-865, 2009. [PubMed: 19543227] [Full Text: https://doi.org/10.1038/embor.2009.94]
Su, L.-K., Burrell, M., Hill, D. E., Gyuris, J., Brent, R., Wiltshire, R., Trent, J., Vogelstein, B., Kinzler, K. W. APC binds to the novel protein EB1. Cancer Res. 55: 2972-2977, 1995. [PubMed: 7606712]
Su, L.-K., Qi, Y. Characterization of human MAPRE genes and their proteins. Genomics 71: 142-149, 2001. [PubMed: 11161807] [Full Text: https://doi.org/10.1006/geno.2000.6428]
Sun, L., Gao, J., Dong, X., Liu, M., Li, D., Shi, X., Dong, J.-T., Lu, X., Liu, C. EB1 promotes Aurora-B kinase activity through blocking its inactivation by protein phosphatase 2A. Proc. Nat. Acad. Sci. 105: 7153-7158, 2008. Note: Erratum: Proc. Nat. Acad. Sci. 105: 9129 only, 2008. [PubMed: 18477699] [Full Text: https://doi.org/10.1073/pnas.0710018105]
Tanenbaum, M. E., Macurek, L., van der Vaart, B., Galli, M., Akhmanova, A., Medema, R. H. A complex of Kif18b and MCAK promotes microtubule depolymerization and is negatively regulated by Aurora kinases. Curr. Biol. 21: 1356-1365, 2011. [PubMed: 21820309] [Full Text: https://doi.org/10.1016/j.cub.2011.07.017]
Tirnauer, J. S., Bierer, B. E. EB1 proteins regulate microtubule dynamics, cell polarity, and chromosome stability. J. Cell Biol. 149: 761-766, 2000. [PubMed: 10811817] [Full Text: https://doi.org/10.1083/jcb.149.4.761]
Ward, T., Wang, M., Liu, X., Wang, Z., Xia, P., Chu, Y., Wang, X., Liu, L., Jiang, K., Yu, H., Yan, M., Wang, J., Hill, D. L., Huang, Y., Zhu, T., Yao, X. Regulation of a dynamic interaction between two microtubule-binding proteins, EB1 and TIP150, by the mitotic p300/CBP-associated factor (PCAF) orchestrates kinetochore microtubule plasticity and chromosome stability during mitosis. J. Biol. Chem. 288: 15771-15785, 2013. [PubMed: 23595990] [Full Text: https://doi.org/10.1074/jbc.M112.448886]