Alternative titles; symbols
HGNC Approved Gene Symbol: MTUS2
Cytogenetic location: 13q12.3 Genomic coordinates (GRCh38): 13:28,819,963-29,505,947 (from NCBI)
MTUS2 is a microtubule (MT)-binding protein involved in facilitating accurate chromosome movements and orchestrating cellular dynamics and chromosome stability during mitosis (Ward et al., 2013).
By sequencing clones obtained from a size-fractionated human brain cDNA library, Nagase et al. (1998) cloned MTUS2, which they designated KIAA0774. The deduced protein contains 1,163 amino acids. RT-PCR ELISA of human tissues detected high KIAA0774 expression in heart, moderate expression in brain, pancreas, and ovary, low expression in testis, liver, and lung, and little to no expression kidney, skeletal muscle, and spleen.
By database analysis, Jiang et al. (2009) identified MTUS2, which they termed TIP150, as a putative microtubule plus-end tracking protein. TIP150 contains 2 tandem EB1 (MAPRE1; 603108)-binding domains and a putative C-terminal coiled-coil domain. TIP150 orthologs are present in vertebrates, but not in invertebrates, plants, or fungi. TIP150 formed a dimer through the interaction of its C-terminal coiled-coil domain.
By microarray analysis, Du Puy et al. (2009) identified MTUS2, which they called CAZIP, based on its upregulation as human embryonic stem cells (hESCs) differentiated toward cardiomyocytes. CAZIP is conserved among vertebrates, with human CAZIP sharing 69% and 48% amino acid identity with its mouse and chicken orthologs, respectively. Du Puy et al. (2009) identified 2 splice variants of mouse Cazip, with the longer variant encoding a 1,354-amino acid isoform (CazipA) and the shorter variant encoding a 358-amino acid isoform (CazipB). Both isoforms contain a predicted C-terminal leucine-zipper domain. In situ hybridization showed that Cazip was expressed in limb and in heart and nervous system tissues during mouse and chicken embryonic development. Northern blot analysis detected Cazip transcripts of approximately 7 kb (CazipA) and 4.5 kb (CazipB) in adult mouse brain. However, in adult heart, only the smaller transcript was detected, and it was expressed at a higher level in than in brain. Cazip expression was not observed in other adult mouse tissues examined by Northern blot analysis. RT-PCR analysis showed Cazip expression in heart, brain, and eye of mice. CazipA was highly expressed in brain and eye, with lower levels in adult and embryonic heart. CazipB showed higher expression in heart compared with brain and eye. Immunofluorescence analysis revealed that mouse CazipB localized in cytoplasm and subnuclear structures of transfected COS-1 cells.
Gross (2021) mapped the MTUS2 gene to chromosome 13q12.3 based on an alignment of the MTUS2 sequence (GenBank BC119654) with the genomic sequence (GRCh38).
Using various binding assays in human cells, Jiang et al. (2009) showed that TIP150 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 aurora B (AURKB; 604970)-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 knockdown analysis in HeLa cells, Ward et al. (2013) showed that TIP150 was essential for accurate chromosome congression and alignment to the metaphase plate during mitosis. TIP150 regulated spindle MT plus-end dynamics and was required for chromosome biorientation and kinetochore MT dynamics. 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.
Du Puy, L., Beqqali, A., Monshouwer-Kloots, J., Haagsman, H. P., Roelen, B. A. J., Passier, R. CAZIP, a novel protein expressed in the developing heart and nervous system. Dev. Dyn. 238: 2903-2911, 2009. [PubMed: 19806667] [Full Text: https://doi.org/10.1002/dvdy.22107]
Gross, M. B. Personal Communication. Baltimore, Md. 5/28/2021.
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]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 277-286, 1998. [PubMed: 9872452] [Full Text: https://doi.org/10.1093/dnares/5.5.277]
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]