NEK7 regulates dendrite morphogenesis in neurons via Eg5-dependent microtubule stabilization

Freixo, Francisco; Delgado, Paula Martínez; Manso, Yasmina; Sánchez-Huertas, Carlos; Lacasa, Cristina; Soriano, Eduardo; Roig, Joan; Lüders, Jens

doi:10.1038/s41467-018-04706-7

Cited by 36 publications

(40 citation statements)

References 68 publications

(97 reference statements)

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“…Although the mechanism for microtubule stabilization remains to be determined, we found that inhibition of the microtubule-based kinesin motor Eg5 with STLC also blocked this morphological change ( Fig. 1F), in line with recent reports that Eg5 promotes microtubule stabilization in post-mitotic neurons 34 . Hence, activation of NEK9 leads to a microtubuledependent change in interphase cell morphology characterised by formation of elongated cytoplasmic protrusions that contain both actin and stabilised microtubules.…”

Section: Constitutively Active Nek9 Leads To Microtubule-dependent Chsupporting

confidence: 92%

“…Of particular interest to our findings, a kinasedependent role was recently described for NEK7 in stimulating dendrite growth in post-mitotic neurons. This resulted from phosphorylation by NEK7 of the kinesin motor protein Eg5, which in turn led to stabilization of microtubules 34 . Supporting a similar mechanism of action in cancer cells, we found that Eg5 was required for the altered cell morphology induced by activated NEK9.…”

Section: Discussionmentioning

confidence: 99%

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EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer

O’Regan

Barone

Adib

et al. 2019

Preprint

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EML4-ALK is an oncogenic fusion present in ~5% lung adenocarcinomas. However, distinct EML4-ALK variants differ in the length of the EML4 microtubule-associated protein encoded within the fusion and are associated with a poorly understood variability in disease progression and therapeutic response. Here, we show that EML4-ALK variant 3, which is linked to accelerated metastatic spread and worse patient outcome, causes microtubule stabilization, formation of extended cytoplasmic protrusions, loss of cell polarity and increased cell migration. Strikingly, this is dependent upon the NEK9 kinase that interacts with the Nterminal region of EML4. Overexpression of wild-type EML4, as well as constitutive activation of NEK9, also perturbs cell morphology and accelerates cell migration in a manner that requires the downstream kinase NEK7 but not ALK activity. Moreover, elevated NEK9 is associated in patients with EML4-ALK V3 expression, as well as reduced progression-free and overall survival. Hence, we propose that EML4-ALK V3 promotes microtubule stabilization through recruitment of NEK9 and NEK7 to increase cell migration and that this represents a novel actionable pathway that drives disease progression in lung cancer.

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Section: Constitutively Active Nek9 Leads To Microtubule-dependent Chsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer

O’Regan

Barone

Adib

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…A proteomic study found that NEK7 was upregulated in differentiating neurons [157]. Curiously, downregulation of NEK7 expression was shown to lead to defects during neuron differentiation.…”

Section: Nek7mentioning

confidence: 99%

Checking NEKs: Overcoming a Bottleneck in Human Diseases

et al. 2020

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In previous years, several kinases, such as phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular-signal-regulated kinase (ERK), have been linked to important human diseases, although some kinase families remain neglected in terms of research, hiding their relevance to therapeutic approaches. Here, a review regarding the NEK family is presented, shedding light on important information related to NEKs and human diseases. NEKs are a large group of homologous kinases with related functions and structures that participate in several cellular processes such as the cell cycle, cell division, cilia formation, and the DNA damage response. The review of the literature points to the pivotal participation of NEKs in important human diseases, like different types of cancer, diabetes, ciliopathies and central nervous system related and inflammatory-related diseases. The different known regulatory molecular mechanisms specific to each NEK are also presented, relating to their involvement in different diseases. In addition, important information about NEKs remains to be elucidated and is highlighted in this review, showing the need for other studies and research regarding this kinase family. Therefore, the NEK family represents an important group of kinases with potential applications in the therapy of human diseases.

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“…Recently, Nek7 has been found to be essential for MT nucleation (Kim et al, 2007), MT stabilization through Eg5 (Freixo et al, 2018), and to play a role in MT stability and dynamics (Cohen et al, 2013). The authors showed that Nek7 increases the growth and depolymerization velocity of MT and lengthens time of catastrophe.…”

Section: Discussionmentioning

confidence: 99%

Evidence of Presence and Activation of the two Cell Cycle Kinases Nek6 and Nek7 in the ciliated Neuroretina

et al. 2020

Preprint

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The serine/threonine NIMA kinases are widely found in eukaryotes. They are cell-cycle kinases that are associated with centrosomes and spindle apparatus and cilia. In cilia, NIMA kinases are reported to play a role in cilia length maintenance and deflagelation. Here we focus on the two Nek homologs, Nek6 and Nek7, and their potential role in retina. We report for the first-time expression of nek6 and nek7 mRNA and protein in retinal tissue. In particular, we detect localisation of these kinases to photoreceptors outer segments. Moreover, we are able to show a light-dependent phosphorylation of the activation loop (serine 206) of Nek6/7 in rod outer segments, suggesting activation of these kinases is downstream of the phototransduction pathway. Indeed, we demonstrate that Nek6/7 phosphorylation in the retina is dependent on Grk1 function. Furthermore, Nek6/7 phosphorylation can be stimulated in the brain by opiate drugs, suggesting that activation of Nek6/7 lies downstream of G protein coupled receptors activation, in general. Nek6/7 may couple photoreception with outer segment biogenesis through phosphorylation of downstream substrates, which may affect the microtubules of the axoneme.

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NEK7 regulates dendrite morphogenesis in neurons via Eg5-dependent microtubule stabilization

Cited by 36 publications

References 68 publications

EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer

EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer

Checking NEKs: Overcoming a Bottleneck in Human Diseases

Evidence of Presence and Activation of the two Cell Cycle Kinases Nek6 and Nek7 in the ciliated Neuroretina

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