Differential Signature of the Centrosomal MARK4 Isoforms in Glioma

Abstract

Abstract.Background: MAP/microtubule affinity-regulating kinase 4 (MARK4) is a serine-threonine kinase expressed in two spliced isoforms, MARK4L and MARK4S, of which MARK4L is a candidate for a role in neoplastic transformation.Methods: We performed mutation analysis to identify sequence alterations possibly affecting MARK4 expression. We then investigated the MARK4L and MARK4S expression profile in 21 glioma cell lines and 36 tissues of different malignancy grades, glioblastoma-derived cancer stem cells (GBM CSCs) and mouse neural stem cells (NSCs) by real-time PCR, immunoblotting and immunohistochemistry. We also analyzed the sub-cellular localisation of MARK4 isoforms in glioma and normal cell lines by immunofluorescence.Results: Mutation analysis rules out sequence variations as the cause of the altered MARK4 expression in glioma. Expression profiling confirms that MARK4L is the predominant isoform, whereas MARK4S levels are significantly decreased in comparison and show an inverse correlation with tumour grade. A high MARK4L/MARK4S ratio also characterizes undifferentiated cells, such as GBM CSCs and NSCs. Accordingly, only MARK4L is expressed in brain neurogenic regions. Moreover, while both MARK4 isoforms are localised to the centrosome and midbody in glioma and normal cells, the L isoform exhibits an additional nucleolar localisation in tumour cells.Conclusions: The observed switch towards MARK4L suggests that the balance between the MARK4 isoforms is carefully guarded during neural differentiation but may be subverted in gliomagenesis. Moreover, the MARK4L nucleolar localisation in tumour cells features this MARK4 isoform as a nucleolus-associated tumour marker.

LINC00673 is activated by YY1 and promotes the proliferation of breast cancer cells via the miR-515-5p/MARK4/Hippo signaling pathway

“…Here, we used RNA-seq to identify the regulatory networks of mRNAs and noncoding RNAs in breast cancer. Among the results from the analysis of potential mRNA interactions, MARK4 sparked our interest since it is associated with tumorigenesis [49,50]. Previous studies showed that MARK4 attenuates the proliferation and migration of MDA-MB-231 cells via the Hippo signaling pathway [39].…”

Par-1 Regulates Tissue Growth by Influencing Hippo Phosphorylation Status and Hippo-Salvador Association

“…Our study suggested that Par-1 may have a procarcinogenic role because its hyperactivation in Drosophila is sufficient to induce tissue overgrowth, and in mammals, Par-1 is sufficient to activate YAP. Interestingly, MARK4 has been suggested to play a role in hepatocellular carcinogenesis and gliomagenesis [51],[52]. However, whether MARK1 is also involved in carcinogenesis is largely unknown.…”

“…Hyper-phosphorylation of the microtubule-associated protein Tau by microtubule affinity regulating kinase, the homolog of Drosophila Par-1 (MARK) [48], which is activated by upstream kinases, such as LKB1 [49] and Tao-1 [50], results in microtubule depolymerization and abnormal aggregation of Tau in Alzheimer disease. Additionally, MARK4 has been reported to be involved in hepatocellular carcinogenesis and gliomagenesis [51],[52].…”

Centrosome Dysfunction Contributes to Chromosome Instability, Chromoanagenesis, and Genome Reprograming in Cancer

“…Nevertheless, despite their common occurrence, and perhaps due to the heterogeneity of centrosome abnormalities in cancer, it has been difficult to determine whether centrosomes abnormalities are caused by primary intrinsic centrosome defects, or are the consequence of dysfunction of other cellular processes that lead to the accumulation of normally replicated centrosomes, such as for instance in cases of cell division failure ( 271 , 272 ). In consequence a considerable volume of ongoing research is being devoted to elucidating in detail the molecular pathways involved in centrosome dysfunction in cancer, their impact on the cancer genome, and the prospects of utilizing centrosome defects as biomarkers ( 205 , 273 , 274 ) and targets for cancer specific therapy ( 275 – 279 ).…”