MARK4 Is a Novel Microtubule-associated Proteins/Microtubule Affinity-regulating Kinase That Binds to the Cellular Microtubule Network and to Centrosomes

Trinczek, Bernhard; Brajenovic, Miro; Ebneth, Andreas; Drewes, Gerard

doi:10.1074/jbc.m304528200

Cited by 165 publications

(188 citation statements)

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“…However, in this case the actin stress fibers are not rendered dynamic, and consequently focal adhesions are preserved and filopodia do not evolve ( Figure 7B, 3, 6, and 9). This experiment shows that active PAK5 NE has two independent effects on the cytoskel- The colocalization is concentrated on the pericentriolar region (merge, 9, arrows), reminiscent of MARK4 (Trinczek et al, 2004). The highest coincidence is observed with wild-type PAK5.…”

Section: Pak5 Inhibits Mark2 and Regulates The Stability Of Microtubumentioning

confidence: 69%

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PAK5 Kinase Is an Inhibitor of MARK/Par-1, Which Leads to Stable Microtubules and Dynamic Actin

Matenia

Griesshaber

et al. 2005

MBoC

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MARK/Par-1 is a kinase involved in development of embryonic polarity. In neurons, MARK phosphorylates tau protein and causes its detachment from microtubules, the tracks of axonal transport. Because the target sites of MARK on tau occur at an early stage of Alzheimer neurodegeneration, we searched for interaction partners of MARK. Here we report that MARK2 is negatively regulated by PAK5, a neuronal member of the p21-activated kinase family. PAK5 suppresses the activity of MARK2 toward its target, tau protein. The inhibition requires the binding between the PAK5 and MARK2 catalytic domains, but does not require phosphorylation. In transfected Chinese hamster ovary (CHO) cells both kinases show a vesicular distribution with partial colocalization on endosomes containing AP-1/2. Although MARK2 transfected alone destabilizes microtubules and stabilizes actin stress fibers, PAK5 keeps microtubules stable through the downregulation of MARK2 but destabilizes the F-actin network so that stress fibers and focal adhesions disappear and cells develop filopodia. The results point to an inverse relationship between actin-and microtubule-related signaling by the PAK5 and MARK2 pathways that affect both cytoskeletal networks. INTRODUCTIONThe observations reported here originated from a study of the neuronal microtubule-associated protein tau and its abnormal changes in Alzheimer's disease. The function of tau in healthy neurons is to stabilize microtubules and to ensure axonal transport along microtubules. In degenerating neurons, tau is hyperphosphorylated, detaches from microtubules, and aggregates into pathological "paired helical filaments." The detachment from microtubules is achieved most efficiently by phosphorylating the KXGS-motifs in the microtubule-binding domain of tau, and elevated phosphorylation at these sites occurs early in Alzheimer's disease (Augustinack et al., 2002). A search for the responsible kinase lead to the identification of the MARK family of protein kinases (Drewes et al., 1997). They are related to the Par-1 kinases in Caenorhabditis elegans and Drosophila melanogaster, which are involved in the determination of embryonic polarity (reviews, Pellettieri and Seydoux, 2002;Fortini, 2004), and indeed the activity of MARK is important for neuronal polarity as well (Biernat et al., 2002). MARK kinases consist of an N-terminal catalytic domain, followed by UBA, spacer, and tail domains. One requirement for activity is the phosphorylation of a threonine in the activation loop (T208 in MARK2), which keeps the active site accessible to the substrate. In the case of MARKs from mammalian brain this is achieved by the kinase MARKK (Timm et al., 2003). Its activation, like that of MARK, leads to detachment of tau and neuronal degeneration, and similar principles appear to hold for other organisms (Nishimura et al., 2004). On the other hand, as with other multidomain kinases, regulation is likely to take place on several levels (Huse and Kuriyan, 2002). Examples are the binding of a pseudosubstrate peptide int...

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Section: Pak5 Inhibits Mark2 and Regulates The Stability Of Microtubumentioning

confidence: 69%

“…(7-9) Similar experiment with inactive YFP-PAK5 MM . The colocalization is concentrated on the pericentriolar region (merge, 9, arrows), reminiscent of MARK4 (Trinczek et al, 2004). The highest coincidence is observed with wild-type PAK5.…”

Section: Pak5 Inhibits Mark2 and Regulates The Stability Of Microtubumentioning

confidence: 76%

PAK5 Kinase Is an Inhibitor of MARK/Par-1, Which Leads to Stable Microtubules and Dynamic Actin

Matenia

Griesshaber

et al. 2005

MBoC

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“…We identified 5 transcripts down‐regulated upon miR‐515‐5p overexpression: NRAS, FZD4, CDC42BPA, PIK3C2B and MARK4 (Fig 2A), and these were validated by qPCR (Fig 2B and C). These transcripts have been described as being involved in cell migration and are predicted by TargetScan to be directly targeted by miR‐515‐5p 6, 12, 13, 14, 15. Furthermore, we validated this using luciferase report assays that demonstrated that miR‐515‐5p interacts directly with the 3′ UTR of NRAS, PIK3C2B and MARK4 (Fig 2E and F) and showed the same targets to be down‐regulated by miR‐515‐5p in NSCLC cells (Fig 2D).…”

Section: Discussionmentioning

confidence: 99%

miR‐515‐5p controls cancer cell migration throughMARK4 regulation

et al. 2016

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Here, we show that miR‐515‐5p inhibits cancer cell migration and metastasis. RNA‐seq analyses of both oestrogen receptor receptor‐positive and receptor‐negative breast cancer cells overexpressing miR‐515‐5p reveal down‐regulation of NRAS, FZD4, CDC42BPA, PIK3C2B and MARK4 mRNAs. We demonstrate that miR‐515‐5p inhibits MARK4 directly 3′ UTR interaction and that MARK4 knock‐down mimics the effect of miR‐515‐5p on breast and lung cancer cell migration. MARK4 overexpression rescues the inhibitory effects of miR‐515‐5p, suggesting miR‐515‐5p mediates this process through MARK4 down‐regulation. Furthermore, miR‐515‐5p expression is reduced in metastases compared to primary tumours derived from both in vivo xenografts and samples from patients with breast cancer. Conversely, miR‐515‐5p overexpression prevents tumour cell dissemination in a mouse metastatic model. Moreover, high miR‐515‐5p and low MARK4 expression correlate with increased breast and lung cancer patients' survival, respectively. Taken together, these data demonstrate the importance of miR‐515‐5p/MARK4 regulation in cell migration and metastasis across two common cancers.

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“…For the detection of NGC, cells were incubated with either monoclonal anti-NGC antibody C5 (30) or polyclonal rabbit anti-NGC antiserum (30). For the staining of tubulin, cells were treated as described (31) and incubated with monoclonal anti-␤-tubulin antibody (clone2-28-33, Sigma). Cells were also stained by monoclonal anti-Myc tag antibody (clone 9E10, Upstate Biotechnology, Lake Placid, NY).…”

Section: Methodsmentioning

confidence: 99%

Neuroglycan C Is a Novel Midkine Receptor Involved in Process Elongation of Oligodendroglial Precursor-like Cells

Ichihara-Tanaka

Oohira

Rumsby

et al. 2006

Journal of Biological Chemistry

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Midkine is a heparin-binding growth factor that promotes cell attachment and process extension in undifferentiated bipolar CG-4 cells, an oligodendroglial precursor cell line. We found that CG-4 cells expressed a non-proteoglycan form of neuroglycan C, known as a part-time transmembrane proteoglycan. We demonstrated that neuroglycan C before or after chondroitinase ABC treatment bound to a midkine affinity column. Neuroglycan C lacking chondroitin sulfate chains was eluted with 0.5 M NaCl as a major fraction from the column. We confirmed that CG-4 cells expressed two isoforms of neuroglycan C, I, and III, by isolating cDNA. Among three functional domains of the extracellular part of neuroglycan C, the chondroitin sulfate attachment domain and acidic amino acid cluster box domain showed affinity for midkine, but the epidermal growth factor domain did not. Furthermore, cell surface neuroglycan C could be cross-linked with soluble midkine. Process extension on midkine-coated dishes was inhibited by either a monoclonal antineuroglycan C antibody C1 or a glutathione S-transferase-neuroglycan C fusion protein. Finally, stable transfectants of B104 neuroblastoma cells overexpressing neuroglycan C-I or neuroglycan C-III attached to the midkine substrate, spread well, and gave rise to cytoskeletal changes. Based on these results, we conclude that neuroglycan C is a novel component of midkine receptors involved in process elongation. Midkine (MK),2 a heparin-binding growth factor, is strongly expressed at the mid-embryonic stage of development and is preferentially expressed in the kidney after birth (1, 2). MK is a 13-kDa protein with about 50% sequence identity to pleiotrophin (PTN), which is also called heparin-binding growth-associated molecule (3, 4). MK promotes neurite outgrowth and migration in neuronal cells isolated from the embryonic brain (5-7) and prevents apoptosis (8, 9). MK also promotes the migration of inflammatory leukocytes (10) and thereby plays a key role in the etiology of neointima formation (10), renal injury (11, 12), rheumatoid arthritis (13), and intraperitoneal adhesion after surgery (14). So far, protein-tyrosine phosphatase (7, 15), anaplastic lymphoma kinase (16), low density-lipoprotein receptor-related protein-1 (17), low density lipoprotein receptor-related protein 6 (9), and integrin ␣4␤1 and ␣6␤1 (18) have been identified as MK receptors. These molecules cooperate during MK signaling, possibly as a receptor complex (18). However, not all the molecules serving as MK receptors have been clarified. Importantly, we do not know whether a function specific to a class of cells such as neurite extension requires another receptor to transmit the specific signal or not. Here, we report that a cell surface molecule is specifically expressed in the nervous system as a component of the MK receptor in cells extending processes.When undifferentiated CG-4 cells, an oligodendrocyte precursor cell line, are cultured on dishes coated with MK or PTN, they quickly extend processes and adopt bipolar shapes ...

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MARK4 Is a Novel Microtubule-associated Proteins/Microtubule Affinity-regulating Kinase That Binds to the Cellular Microtubule Network and to Centrosomes

Cited by 165 publications

References 58 publications

PAK5 Kinase Is an Inhibitor of MARK/Par-1, Which Leads to Stable Microtubules and Dynamic Actin

PAK5 Kinase Is an Inhibitor of MARK/Par-1, Which Leads to Stable Microtubules and Dynamic Actin

miR‐515‐5p controls cancer cell migration throughMARK4 regulation

Neuroglycan C Is a Novel Midkine Receptor Involved in Process Elongation of Oligodendroglial Precursor-like Cells

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