EML4 and NUDC in mitotic spindle formation

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R-HSA-9648025
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Homo sapiens
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EML4 and NUDC proteins are required for mitotic spindle formation, attachment of spindle microtubule ends to kinetochores, and alignment of mitotic chromosome at the metaphase plate. EML4 is a WD40 family protein that binds to interphase microtubules and stabilizes them (Houtman et al. 2007, Adib et al. 2019). At mitotic entry, EML4 undergoes phosphorylation (Pollmann et al. 2006, Adib et al. 2019) by serine/threonine kinases NEK6 and NEK7, leading to its dissociation from microtubules, which is necessary for the assembly of a dynamic mitotic spindle (Adib et al. 2019). EML4, through its WD40 repeats, interacts with NUDC and recruits it to the kinetochores of the mitotic spindle (Chen et al. 2015). It is possible that other mitotic kinases, besides NEK6 and NEK7, also phosphorylate EML4. Phosphorylation of different residues of EML4 could reduce or increase affinity of EML4 for specific subpopulations of microtubules in mitosis.
A recurrent genomic rearrangement, reported in about 5% cases of non-small cell lung cancer (NSCLC) fuses the N-terminal portion of EML4 with the C-terminal portion of ALK (anaplastic lymphoma kinase), resulting in a constitutively active ALK (Soda et al. 2007, Richards et al. 2015).

Literature References
PubMed ID Title Journal Year
17625570 Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer

Ishikawa, Y, Watanabe, H, Hatanaka, H, Soda, M, Sugiyama, Y, Takada, S, Choi, YL, Yamashita, Y, Aburatani, H, Niki, T, Enomoto, M, Mano, H, Fujiwara, S, Ishikawa, S, Ohno, S, Bando, M, Kurashina, K, Sohara, Y

Nature 2007
25740311 Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain

O'Regan, L, Richards, MW, Bayliss, R, Fry, AM, Straube, A, Montgomery, JM, Roth, D

Biochem. J. 2015
25789526 EML4 promotes the loading of NUDC to the spindle for mitotic progression

Hyodo, T, Ito, S, Chen, D, Yuan, H, Hamaguchi, M, Kadomatsu, K, Senga, T

Cell Cycle 2015
17196341 Echinoderm microtubule-associated protein like protein 4, a member of the echinoderm microtubule-associated protein family, stabilizes microtubules

De Zeeuw, CI, Houtman, SH, Rutteman, M, French, PJ

Neuroscience 2007
31409757 Mitotic phosphorylation by NEK6 and NEK7 reduces the microtubule affinity of EML4 to promote chromosome congression

O'Regan, L, Atherton, J, Straatman, KR, Richards, MW, Bayliss, R, Fry, AM, Straube, A, Moores, CA, Montgomery, JM, Roth, D, Adib, R

Sci Signal 2019
16890222 Human EML4, a novel member of the EMAP family, is essential for microtubule formation

Buck, F, Heidebrecht, HJ, Kruse, ML, Pollmann, M, Parwaresch, R, Adam-Klages, S

Exp. Cell Res. 2006
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