The potential role of the NEK6, AURKA, AURKB, and PAK1 genes in adenomatous colorectal polyps and colorectal adenocarcinoma

Kasap, Elmas; Gerçeker, Emre; Boyacioglu, Sedat; Yüceyar, Hakan; Yıldırm, Hatice; Ayhan, Semin; Korkmaz, Mehmet

doi:10.1007/s13277-015-4131-6

Cited by 27 publications

(22 citation statements)

References 35 publications

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“…Our data establishing AURKA as a substrate of VHL presents new opportunities for intervention, not only in RCC, but also in other cancers such as colorectal carcinoma, where genomic data from patients reveals the existence of VHL mutations, 48, 49 elevated AURKA 50 and ciliary defects. 51 Importantly, our demonstration that primary cilia can be rescued with AURKA and HDAC6 inhibitors provides proof-of-concept that targeting the VHL–AURKA–HDAC6 axis may have therapeutic efficacy.…”

Section: Discussionmentioning

confidence: 75%

Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL

et al. 2017

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The hypoxia-regulated tumor-suppressor von Hippel-Lindau (VHL) is an E3 ligase that recognizes its substrates as part of an oxygen-dependent prolyl hydroxylase (PHD) reaction, with hypoxia-inducible factor α (HIFα) being its most notable substrate. Here we report that VHL has an equally important function distinct from its hypoxia-regulated activity. We find that Aurora kinase A (AURKA) is a novel, hypoxia-independent target for VHL ubiquitination. In contrast to its hypoxia-regulated activity, VHL mono-, rather than poly-ubiquitinates AURKA, in a PHD-independent reaction targeting AURKA for degradation in quiescent cells, where degradation of AURKA is required to maintain the primary cilium. Tumor-associated variants of VHL differentiate between these two functions, as a pathogenic VHL mutant that retains intrinsic ability to ubiquitinate HIFα is unable to ubiquitinate AURKA. Together, these data identify VHL as an E3 ligase with important cellular functions under both normoxic and hypoxic conditions.

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Section: Discussionmentioning

confidence: 75%

Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL

et al. 2017

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“…Given these collective observations, we propose that the control of intracellular trafficking may be an ancient and conserved function for members of the NIMA kinase family. This would represent a role for mammalian NEK kinases that has been largely overlooked but could be relevant to their involvement in diseases including cancer and ciliopathies [23,[92][93][94][95][96][97][98][99][100][101][102][103][104][105][106]. Future studies in both C. elegans and mammalian systems will be important to establish the precise functions of NIMA-related kinases in cellular trafficking and human disease processes.…”

Section: Trafficking Functions Of Nima Kinase Family Members Are Likementioning

confidence: 99%

Control of clathrin-mediated endocytosis by NIMA family kinases

et al. 2020

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Endocytosis, the process by which cells internalize plasma membrane and associated cargo, is regulated extensively by posttranslational modifications. Previous studies suggested the potential involvement of scores of protein kinases in endocytic control, of which only a few have been validated in vivo. Here we show that the conserved NIMA-related kinases NEKL-2/NEK8/9 and NEKL-3/NEK6/7 (the NEKLs) control clathrin-mediated endocytosis in C. elegans. Loss of NEKL-2 or NEKL-3 activities leads to penetrant larval molting defects and to the abnormal localization of trafficking markers in arrested larvae. Using an auxin-based degron system, we also find that depletion of NEKLs in adult-stage C. elegans leads to gross clathrin mislocalization and to a dramatic reduction in clathrin mobility at the apical membrane. Using a non-biased genetic screen to identify suppressors of nekl molting defects, we identified several components and regulators of AP2, the major clathrin adapter complex acting at the plasma membrane. Strikingly, reduced AP2 activity rescues both nekl mutant molting defects as well as associated trafficking phenotypes, whereas increased levels of active AP2 exacerbate nekl defects. Moreover, in a unique example of mutual suppression, NEKL inhibition alleviates defects associated with reduced AP2 activity, attesting to the tight link between NEKL and AP2 functions. We also show that NEKLs are required for the clustering and internalization of membrane cargo required for molting. Notably, we find that human NEKs can rescue molting and trafficking defects in nekl mutant worms, suggesting that the control of intracellular trafficking is an evolutionarily conserved function of NEK family kinases.

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“…In recent years, altered expression and activity of NEK6 were associated with several types of cancer, such as liver [139], prostate [140], gastric [141][142][143], colorectal [144,145], breast [146], serous epithelial ovarian [147], thyroid [148], and retinoblastoma cancers [149]. In addition, inflammation-based diseases, such as ulcerative colitis, have also been linked to NEK6 [28].…”

Section: Nek6mentioning

confidence: 99%

“…The main risk factor for the development of colorectal adenocarcinoma (CRC) is the emergence of colorectal adenomatous polyps (CRAP), which are benign tumors that can progress to cancer through various genetic and epigenetic changes [144]. Kasap et al (2016) identified that NEK6 and other genes, such as AURKA, AURKB, HDAC1, and PAK1, are significantly overexpressed in samples from patients with CRC and CRAP. In addition, larger diameter polyps showed greater overexpression of NEK6 compared to smaller polyps [145].…”

Section: Nek6mentioning

confidence: 99%

“…Kasap et al (2016) identified that NEK6 and other genes, such as AURKA, AURKB, HDAC1, and PAK1, are significantly overexpressed in samples from patients with CRC and CRAP. In addition, larger diameter polyps showed greater overexpression of NEK6 compared to smaller polyps [145]. All these findings show that NEK6 may be a predictive marker that can be used to determine the time of surveillance between the removal of polyps and the next colonoscopy.…”

Section: Nek6mentioning

confidence: 99%

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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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The potential role of the NEK6, AURKA, AURKB, and PAK1 genes in adenomatous colorectal polyps and colorectal adenocarcinoma

Cited by 27 publications

References 35 publications

Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL

Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL

Control of clathrin-mediated endocytosis by NIMA family kinases

Checking NEKs: Overcoming a Bottleneck in Human Diseases

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