Protein kinase which influences neuronal morphogenesis and polarity through effects on microtubules. Regulates microtubule acetylation in neurons. Contributes to prolactin-mediated phosphorylation of PXN and VAV2. Implicated in prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells through mechanisms involving RAC1 activation and phosphorylation of PXN and VAV2.
Prolactin (PRL) receptor activation contributes to the progression and motility of human breast cancer. This event activates multimeric signaling pathways, including the activation of the Vav family of guanine nucleotide exchange factors. To detect novel proteins interacting with Vav, yeast two-hybrid analysis was performed and demonstrated an interaction between the serine/threonine NIMA (never in mitosis A)-related family kinase p56Nek3 and Vav1. The PRL-dependent interaction of Nek3 with Vav1 and Vav2 was confirmed by coimmunoprecipitation analysis. PRL stimulation of T47D cells induced Nek3 kinase activity and the interaction of Vav2/Nek3 with the PRL receptor. Increased Nek3 levels up-regulated Vav2 serine and tyrosine phosphorylation, whereas knockdown of Nek3 resulted in a reduction of Vav2 phosphorylation. Activation of guanosine triphosphatase Rac-1 in Chinese hamster ovary transfectants required both Nek3 and Vav2 and was inhibited by the overexpression of a kinase inactivating Nek3 mutant. However, overexpression of either Nek3 or kinase-inactive Nek3 had no effect on Vav2-potentiated signal transducer and activator of transcription 5-mediated gene expression. Overexpression of kinase inactive Nek3 in T47D cells led to a 50% increase in apoptosis vs. controls. These data suggest that the PRL-mediated activation of Nek3 contributes differentially to Vav2 signaling pathways involving Rac1 and signal transducer and activator of transcription 5 and implicates Nek3 during PRL-mediated actions in breast cancer.
Prolactin (PRL) stimulates the cytoskeletal re-organization and motility of breast cancer cells. During PRL receptor signaling, Vav2 becomes phosphorylated and activated, an event regulated by the serine/threonine kinase Nek3. Given the regulatory role of Vav2, the function of Nek3 in PRL-mediated motility and invasion was examined. Overexpression of Nek3 in Chinese hamster ovary transfectants potentiated cytoskeletal re-organization in response to PRL. In contrast, downregulation of Nek3 expression by small-interfering RNA (siRNA) attenuated PRL-mediated cytoskeletal reorganization, activation of GTPase Rac1, cell migration and invasion of T47D cells. In addition, PRL stimulation induced an interaction between Nek3 and paxillin and significantly increased paxillin serine phosphorylation, whereas Nek3 siRNA-transfected cells showed a marked reduction in paxillin phosphorylation. Analysis of breast tissue microarrays also demonstrated a significant up-regulation of Nek3 expression in malignant versus normal specimens. These data suggest that Nek3 contributes to PRL-mediated breast cancer motility through mechanisms involving Rac1 activation and paxillin phosphorylation.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionIntAct
Prolactin (PRL) receptor activation contributes to the progression and motility of human breast cancer. This event activates multimeric signaling pathways, including the activation of the Vav family of guanine nucleotide exchange factors. To detect novel proteins interacting with Vav, yeast two-hybrid analysis was performed and demonstrated an interaction between the serine/threonine NIMA (never in mitosis A)-related family kinase p56Nek3 and Vav1. The PRL-dependent interaction of Nek3 with Vav1 and Vav2 was confirmed by coimmunoprecipitation analysis. PRL stimulation of T47D cells induced Nek3 kinase activity and the interaction of Vav2/Nek3 with the PRL receptor. Increased Nek3 levels up-regulated Vav2 serine and tyrosine phosphorylation, whereas knockdown of Nek3 resulted in a reduction of Vav2 phosphorylation. Activation of guanosine triphosphatase Rac-1 in Chinese hamster ovary transfectants required both Nek3 and Vav2 and was inhibited by the overexpression of a kinase inactivating Nek3 mutant. However, overexpression of either Nek3 or kinase-inactive Nek3 had no effect on Vav2-potentiated signal transducer and activator of transcription 5-mediated gene expression. Overexpression of kinase inactive Nek3 in T47D cells led to a 50% increase in apoptosis vs. controls. These data suggest that the PRL-mediated activation of Nek3 contributes differentially to Vav2 signaling pathways involving Rac1 and signal transducer and activator of transcription 5 and implicates Nek3 during PRL-mediated actions in breast cancer.
The serine/threonine protein kinase NIMA of Aspergillus nidulans is required for entry into mitosis and may function in parallel to the universal mitotic inducer p34cdc2. Here, we report the isolation of complementary DNAs encoding Nek2 and Nek3, two novel human protein kinases structurally related to NIMA. Sequence comparisons revealed several unique features which may define a family of NIMA-related protein kinases. Nek2 was chosen for further study since it represents the closest known mammalian relative of NIMA. Chromosomal mapping of the nek2 gene identified two independent loci on chromosomes 1 and 14, and Northern blot analyses revealed the expression of two distinct mRNAs of approximately 2.4 and 4.7 kilobases in all human cell lines examined. In HeLa cells synchronized by both drug arrest and elutriation, a strikingly cell cycle-dependent pattern of Nek2 expression could be observed; Nek2 protein was almost undetectable during G1 but accumulated progressively throughout S, reaching maximal levels in late G2. These observations demonstrate that Nek2 resembles Aspergillus NIMA, not only in its catalytic domain, but also in its cell cycle-dependent expression. Hence, the human Nek2 protein kinase may also function at the onset of mitosis.
The progression of biochemical and morphological phases and events that occur in a cell during successive cell replication or nuclear replication events. Canonically, the cell cycle comprises the replication and segregation of genetic material followed by the division of the cell, but in endocycles or syncytial cells nuclear replication or nuclear division may not be followed by cell division.
A cell cycle process comprising the steps by which the nucleus of a eukaryotic cell divides; the process involves condensation of chromosomal DNA into a highly compacted form. Canonically, mitosis produces two daughter nuclei whose chromosome complement is identical to that of the mother cell.
The serine/threonine protein kinase NIMA of Aspergillus nidulans is required for entry into mitosis and may function in parallel to the universal mitotic inducer p34cdc2. Here, we report the isolation of complementary DNAs encoding Nek2 and Nek3, two novel human protein kinases structurally related to NIMA. Sequence comparisons revealed several unique features which may define a family of NIMA-related protein kinases. Nek2 was chosen for further study since it represents the closest known mammalian relative of NIMA. Chromosomal mapping of the nek2 gene identified two independent loci on chromosomes 1 and 14, and Northern blot analyses revealed the expression of two distinct mRNAs of approximately 2.4 and 4.7 kilobases in all human cell lines examined. In HeLa cells synchronized by both drug arrest and elutriation, a strikingly cell cycle-dependent pattern of Nek2 expression could be observed; Nek2 protein was almost undetectable during G1 but accumulated progressively throughout S, reaching maximal levels in late G2. These observations demonstrate that Nek2 resembles Aspergillus NIMA, not only in its catalytic domain, but also in its cell cycle-dependent expression. Hence, the human Nek2 protein kinase may also function at the onset of mitosis.
Prolactin (PRL) receptor activation contributes to the progression and motility of human breast cancer. This event activates multimeric signaling pathways, including the activation of the Vav family of guanine nucleotide exchange factors. To detect novel proteins interacting with Vav, yeast two-hybrid analysis was performed and demonstrated an interaction between the serine/threonine NIMA (never in mitosis A)-related family kinase p56Nek3 and Vav1. The PRL-dependent interaction of Nek3 with Vav1 and Vav2 was confirmed by coimmunoprecipitation analysis. PRL stimulation of T47D cells induced Nek3 kinase activity and the interaction of Vav2/Nek3 with the PRL receptor. Increased Nek3 levels up-regulated Vav2 serine and tyrosine phosphorylation, whereas knockdown of Nek3 resulted in a reduction of Vav2 phosphorylation. Activation of guanosine triphosphatase Rac-1 in Chinese hamster ovary transfectants required both Nek3 and Vav2 and was inhibited by the overexpression of a kinase inactivating Nek3 mutant. However, overexpression of either Nek3 or kinase-inactive Nek3 had no effect on Vav2-potentiated signal transducer and activator of transcription 5-mediated gene expression. Overexpression of kinase inactive Nek3 in T47D cells led to a 50% increase in apoptosis vs. controls. These data suggest that the PRL-mediated activation of Nek3 contributes differentially to Vav2 signaling pathways involving Rac1 and signal transducer and activator of transcription 5 and implicates Nek3 during PRL-mediated actions in breast cancer.
Protein involved in the complex series of events by which the cell duplicates its contents and divides into two. The eukaryotic cell cycle can be divided in four phases termed G1 (first gap period), S (synthesis, phase during which the DNA is replicated), G2 (second gap period) and M (mitosis). The prokaryotic cell cycle typically involves a period of growth followed by DNA replication, partition of chromosomes, formation of septum and division into two similar or identical daughter cells.
Protein involved in the separation of one cell into two daughter cells. In eukaryotic cells, cell division includes the nuclear division (mitosis) and the subsequent cytoplasmic division (cytokinesis).
Protein involved in mitosis, the nuclear division in eukaryotic cells involving the exact duplication and separation of the chromosome threads so that each daughter nucleus carries a chromosome complement identical to that of the parent nucleus. Mitosis is divided into four substages: prophase, metaphase, anaphase and telophase.
Protein which catalyzes the phosphorylation of serine or threonine residues on target proteins by using ATP as phosphate donor. Such phosphorylation may cause changes in the function of the target protein. Protein kinases share a conserved catalytic core common to both serine/ threonine and tyrosine protein kinases.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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