Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the cloning of a mouse cDNA encoding the MAK-V protein kinase, with a putative specificity for serine/threonine residues. The mak-v gene is transcribed in adult brain and in the mouse embryo from at least 7.5 dpc. Using the yeast two-hybrid system, we showed that MAK-V interacts with Rabaptin-5, a protein which plays an important role in endocytosis. Functional studies of the MAK-V protein suggest that it regulates endocytosis. We also constructed a human mak-v cDNA and localized the human mak-v gene at 21q22.11. Its chromosomal location suggests that mak-v could be involved in disorders of the nervous system, development or in malignancies.
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PMID:The MAK-V protein kinase regulates endocytosis in mouse. 1112 44

Identification of interaction partners opens a way to direct functional characterization of proteins. Several cDNAs coding for potential partners of protein kinase MAK-V/Hunk were isolated using two-hybrid cloning in yeast. Based on the partner properties, MAK-V/Hunk was assumed to play a role in tumorigenesis and tumor progression. With the previous results of two-hybrid cloning, MAK-V/Hunk was shown to participate in vesicular transport.
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PMID:[The use of the two-hybrid cloning in yeast for functional characterization of protein kinase MAK-V]. 1206 35

MAK-V/Hunk is a recently identified MARK/Par-1-related mammalian protein kinase. Although the precise function of this protein kinase is yet to be established, available data suggest its involvement in animals' development and in the physiology of the nervous system. Here we report characterization of a cDNA encoding Xenopus laevis orthologue of MAK-V/Hunk protein kinase, xMAK-V. The in silico analysis also revealed MAK-V/Hunk orthologues in the fish Fugu rubripes and primitive chordate Ciona intestinalis but not in invertebrate species such as Drosophila melanogaster and Caenorhabditis elegans, suggesting that MAK-V/Hunk is a chordate-specific protein kinase. The expression of xmak-v in X. laevis embryos was analyzed using whole-mount in situ hybridization. Expression of xmak-v has been detected in all developmental stages studied including maternal expression in unfertilized eggs. The xmak-v mRNA has a predominant occurrence on the animal hemisphere of the egg, and this pattern of expression is sustained throughout cleavage and blastula stages. At the gastrula stage xmak-v expression is restricted to the ectoderm. In the later stage embryos xmak-v is expressed over the entire embryonic surface including the open neural plate at stage 15 and also in neural tube at stage 22. At tadpole stage xmak-v expression is strong in embryonic epidermis, nervous system and sensory organs, and is also obvious in perisomitic mesoderm and brachial arches.
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PMID:Cloning and developmental expression of MARK/Par-1/MELK-related protein kinase xMAK-V in Xenopus laevis. 1474 Feb 10

MAK-V/Hunk is a MARK/Par-1-related protein kinase, whose function is unknown. We studied the subcellular localization of MAK-V/Hunk in COS-1 cells by immunofluorescence. It has a nucleocytoplasmic distribution and is localized to the centrosome, as indicated by co-localization with gamma-tubulin. A putative kinase-deficient mutant, with a mutation in the invariant lysine residue in the catalytic domain, was not targeted to the nucleus or centrosome. These results suggest that the nuclear and centrosomal targeting of MAK-V/Hunk is specific, and is likely to be coupled to its catalytic activity.
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PMID:Subcellular localization of MAK-V/Hunk protein kinase expressed in COS-1 cells. 1475 68

We propose a system for detection of overproduction of protein kinase MAK-V/Hunk in tumours. MAK-V/ Hunk overproduction is observed in about 50% breast carcinomas. Positive staining is obseved in tumour cells only and has mainly cytoplasmic characteristics. Increased production of MAK-V/Hunk does not correlate with histological type of carcinoma, metastasizing, steroid receptor status (estrogen and progesterone), proliferative activity. Tumours positive for MAK-V/ Hunk were more frequently observed in c-erbB2-positive (3+) tumours than in c-erbB2-negative ones. Overproduction of MAK-V/Hunk in human breast cancer may be used fore more precise molecular typing of this tumour, in particular in case of c-erbB2-positive tumors, however, diagnostic-prognostic value of this new molecular marker needs further studies.
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PMID:[Proteinkinase MAK-V/Hunk as a possible dianostic and prognostic marker of human breast carcinoma]. 1557 76

MAK-V/Hunk is a recently isolated MARK/Par-1-related mammalian protein kinase with yet unknown function. To investigate transcriptional regulation of the mouse mak-v/Hunk gene, we isolated genomic fragment of the mouse mak-v/Hunk promoter region. The mak-v/Hunk promoter has no typical TATA box or CAAT box, is GC-rich and contains CpG-island. Amplification of cDNA ends suggested that transcription initiation site is 156 nt upstream translation initiation site. The 5'-flanking region of the mak-v/Hunk gene was ligated to luciferase reporter gene and possessed functional promoter activity. Luciferase assay with a series of truncated 5'-flanking regions demonstrated the region between nt -508 and -347 has a pronounced stimulating effect on transcription activity. In addition, our data suggest that mak-v/Hunk promoter region might be a target for CpG methylation.
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PMID:[Molecular cloning and characterization of the mouse mak-v/Hunk gene promoter]. 1577 50

Activities of many proteins including protein kinases are often regulated by their dynamic association with specific intracellular compartments. MAK-V is an AMPK-like protein kinase with poorly characterized functions and mechanisms of action. Similarly to many other protein kinases, association of MAK-V with specific intracellular compartments could be essential for its proper functions. In this work, we studied subcellular distribution of exogenously produced and endogenous MAK-V proteins in mammalian cells using biochemical cell fractioning aiming to supplement data on MAK-V intracellular localization studied by immunocytochemical methods. We found that a significant portion of MAK-V protein in mammalian cells is associated with membranes. Moreover, MAK-V expressed in yeast was also targeted to membrane, thus suggesting an evolutionarily conservative mechanism of MAK-V membrane association. Based on the ability of various MAK-V deletion mutants to localize to membrane and comparison of MAK-V amino acid sequences from different species, we suggest a possible mechanism governing MAK-V association with intracellular membranes.
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PMID:Membrane localization of the MAK-V protein kinase. 1839 62

MAK-V protein kinase (also known as HUNK) was discovered more than decade ago but its functions and molecular mechanisms of action still remain mostly unknown. In an attempt to associate MAK-V with particular chains of molecular events, we searched for proteins interacting with the C-terminal domain of MAK-V protein kinase. We identified synaptopodin as a protein interaction partner for MAK-V and confirmed this interaction in various ways. Because synaptopodin is important for dendritic spine formation and plays a role in synaptic plasticity, our results might have significant impact on future studies for understanding the role of MAK-V in cells of the nervous system.
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PMID:Interaction between MAK-V protein kinase and synaptopodin. 2156 52

MAK-V/Hunk is a scantily characterized AMPK-like protein kinase. Recent findings identified MAK-V as a pro-survival and anti-apoptotic protein and revealed its role in embryonic development as well as in tumorigenesis and metastasis. However molecular mechanisms of MAK-V action and regulation of its activity remain largely unknown. We identified Nedd4 as an interaction partner for MAK-V protein kinase. However, this HECT-type E3 ubiquitin ligase is not involved in the control of MAK-V degradation by the ubiquitin-proteasome system that regulates MAK-V abundance in cells. However, Nedd4 in an ubiquitin ligase-independent manner rescued developmental defects in Xenopus embryos induced by MAK-V overexpression, suggesting physiological relevance of interaction between MAK-V and Nedd4. This identifies Nedd4 as the first known regulator of MAK-V function.
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PMID:Identification of Nedd4 E3 ubiquitin ligase as a binding partner and regulator of MAK-V protein kinase. 2274 72

Breast cancer patients who are HER2-positive receive targeted inhibitors to HER2, including trastuzumab and lapatinib. While patients benefit from the use of HER2 inhibitors, many fail therapy and almost all patients become resistant to treatment, indicating a critical need to prevent treatment failure. Several recent studies indicate that activation of autophagy contributes to trastuzumab and lapatinib resistance and demonstrate that impairing autophagy in breast cancer cells is therapeutically beneficial. Moreover, autophagy is mechanistically linked through signaling crosstalk to apoptotic pathways, where activation of one process impacts the other. Therefore, understanding the molecular mechanisms that control these processes may uncover novel areas of therapeutic intervention to combat or prevent resistance in breast cancer. We previously characterized the protein kinase HUNK as a breast cancer-promoting factor in HER2/neu-induced mammary tumor models, in which HUNK supported the survival of HER2/neu-positive tumor cells, likely through the regulation of apoptosis. Because significant crosstalk exists between apoptotic and autophagy proteins, we now examine if HUNK is also able to regulate cell survival through modulation of autophagy using HER2 inhibitor sensitive and resistant breast cancer models. Furthermore, we investigate whether inhibiting HUNK impairs in vivo tumor growth that is initiated by HER2 inhibitor-resistant breast cancer cells. Our findings indicate that therapeutically targeting HUNK is a potential strategy for overcoming resistance and that resistant breast cancer cells maintain HUNK expression to drive tumorigenesis, an observation that is consistent with a pro-survival role for this kinase.
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PMID:Regulation of cell survival by HUNK mediates breast cancer resistance to HER2 inhibitors. 2551 31


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