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 have reported that purified native MAP1B interacts with microtubules but not with microfilaments [Pedrotti and Islam, Cell Motil. Cytoskel. (1995) 30, 301-309]. However, MAP1B can be phosphorylated at multiple sites by casein kinase 11 (CKII) and proline-directed protein kinases (PDPK) and immunoblotting studies show that purified native MAP1B is phosphorylated at least at two CKII sites and at one PDPK site [Pedrotti et al., Biochemistry (1996) 35, 3016-3023]. We now show that phosphorylation affects the in vitro binding of MAP1B with microfilaments. Native MAP1B does not bind to microfilaments but after treatment with alkaline phosphatase the dephosphorylated MAP1B binds and cosediments with microfilaments. Dephosphorylation kinetics suggest that the PDPK site, but not CKII sites, may negatively regulate the interaction with F-actin. The ability of dephosphorylated MAP1B to crosslink microfilaments was also examined and showed that MAP1B exhibits only a weak crosslinking of F-actin when compared with MAP2.
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PMID:Dephosphorylated but not phosphorylated microtubule associated protein MAP1B binds to microfilaments. 869 71

Cultures of cerebellar macroneurons were used to study the pattern of expression, subcellular localization, and function of the neuronal cdk5 activator p35 during laminin-enhanced axonal growth. The results obtained indicate that laminin, an extracellular matrix molecule capable of selectively stimulating axonal extension and promoting MAP1B phosphorylation at a proline-directed protein kinase epitope, selectively stimulates p35 expression, increases its association with the subcortical cytoskeleton, and accelerates its redistribution to the axonal growth cones. Besides, suppression of p35, but not of a highly related isoform designated as p39, by antisense oligonucleotide treatment selectively reduces cdk5 activity, laminin-enhanced axonal elongation, and MAP1b phosphorylation. Taken collectively, the present results suggest that cdk5/p35 may serve as an important regulatory linker between environmental signals (e.g., laminin) and constituents of the intracellular machinery (e.g., MAP1B) involved in axonal elongation.
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PMID:Evidence for the participation of the neuron-specific CDK5 activator P35 during laminin-enhanced axonal growth. 982 44

Neuronal morphogenesis depends on the organization of cytoskeletal elements among which microtubules play a very important role. The organization of microtubules is controlled by the presence of microtubule-associated proteins (MAPs), the activity of which is modulated by phosphorylation and dephosphorylation. One of these MAPs is MAP1B, which is very abundant within growing axons of developing neurons where it is found phosphorylated by several protein kinases including CK2. The expression of MAP1B is notably decreased after neuronal maturation in parallel with a change in the localization of the protein, which becomes largely concentrated in neuronal cell bodies and dendrites. Interestingly, MAP1B remains highly phosphorylated at sites targeted by protein kinase CK2 in mature neurons. We have analyzed the expression and localization of CK2 catalytic subunits along neuronal development. CK2alpha subunit appears early during development whereas CK2alpha' subunit appears within mature neurons at the time of dendrite maturation and synaptogenesis, in parallel with the change in the localization of MAP1B. CK2alpha subunit is found associated with microtubule preparations obtained from either grey matter or white matter from adult bovine brain, whereas CK2alpha' subunit is highly enriched in microtubules obtained from grey matter. These results lend support to the hypothesis that CK2alpha' subunit is concentrated in neuronal cell bodies and dendrites, where it associates with microtubules, thus contributing to the increased phosphorylation of MAP1B in this localization in mature neurons.
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PMID:Distribution of CK2, its substrate MAP1B and phosphatases in neuronal cells. 1009 9

We have recently shown that glycogen synthase kinase 3beta (GSK3beta) phosphorylates the microtubule-associated protein (MAP) 1B in an in vitro kinase assay and in cultured cerebellar granule cells. Mapping studies identified a region of MAP1B high in serine-proline motifs that is phosphorylated by GSK3beta. Here we show that COS cells, transiently transfected with both MAP1B and GSK3beta, express high levels of the phosphorylated isoform of MAP1B (MAP1B-P) generated by GSK3beta. To investigate effects of MAP1B-P on microtubule dynamics, double transfected cells were labelled with antibodies to tyrosinated and detyrosinated tubulin markers for stable and unstable microtubules. This showed that high levels of MAP1B-P expression are associated with the loss of a population of detyrosinated microtubules in these cells. Transfection with MAP1B protected microtubules in COS cells against nocodazole depolymerisation, confirming previous studies. However, this protective effect was greatly reduced in cells containing high levels of MAP1B-P following transfection with both MAP1B and GSK3beta. Since we also found that MAP1B binds to tyrosinated, but not to detyrosinated, microtubules in transfected cells, we propose that MAP1B-P prevents tubulin detyrosination and subsequent conversion of unstable to stable microtubules and that this involves binding of MAP1B-P to unstable microtubules. The highest levels of MAP1B-P are found in neuronal growth cones and therefore our findings suggest that a primary role of MAP1B-P in growing axons may be to maintain growth cone microtubules in a dynamically unstable state, a known requirement of growth cone microtubules during pathfinding. To test this prediction, we reduced the levels of MAP1B-P in neuronal growth cones of dorsal root ganglion cells in culture by inhibiting GSK3beta with lithium. In confirmation of the proposed role of MAP1B-P in maintaining microtubule dynamics we found that lithium treatment dramatically increased the numbers of stable (detyrosinated) microtubules in the growth cones of these neurons.
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PMID:Glycogen synthase kinase 3beta phosphorylation of microtubule-associated protein 1B regulates the stability of microtubules in growth cones. 1050 42

Microtubules (MTs) play an important role in elaboration and maintenance of axonal and dendritic processes. MT dynamics are modulated by MT-associated proteins (MAPs), whose activities are regulated by protein phosphorylation. We found that a member of the c-Jun NH(2)-terminal protein kinase (JNK) subgroup of MAP kinases, JNK1, is involved in regulation of MT dynamics in neuronal cells. Jnk1(-/-) mice exhibit disrupted anterior commissure tract formation and a progressive loss of MTs within axons and dendrites. MAP2 and MAP1B polypeptides are hypophosphorylated in Jnk1(-/-) brains, resulting in compromised ability to bind MTs and promote their assembly. These results suggest that JNK1 is required for maintaining the cytoskeletal integrity of neuronal cells and is a critical regulator of MAP activity and MT assembly.
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PMID:JNK1 is required for maintenance of neuronal microtubules and controls phosphorylation of microtubule-associated proteins. 1268 91

MAP1B is a major microtubule-associated phospho-protein in growing axons and growth cones. Recent findings suggest that glycogen synthase kinase 3beta (GSK-3beta) phosphorylation of MAP1B may act as a molecular switch to regulate microtubule stability during axonogenesis. The effects of lithium, an inhibitor of GSK-3beta, on neurons in culture, are consistent with this suggestion. However, lithium is not a specific inhibitor of GSK-3beta. In the experiments reported here we have compared the effects of lithium with SB-216763, a new, potent and specific inhibitor of GSK-3 that has a different mechanism of action from lithium. We examined the effects of inhibition of GSK-3beta on axonogenesis, microtubule distribution, and growth cone behavior in cultured embryonic chick primary sensory neurons. Both compounds reduced axon elongation rates and increased growth cone size. In addition, both compounds slowed growth cone filopodia dynamics. These behavioral changes correlated with a decrease in MAP1B phosphorylation and an increase in the number of stable microtubules in growth cones. These results suggest that a major role of MAP1B in growing axons and growth cones is to regulate microtubule and actin filament stability. Furthermore, this function is regulated by phosphorylation of MAP1B by GSK-3beta.
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PMID:Inhibition of glycogen synthase kinase 3beta in sensory neurons in culture alters filopodia dynamics and microtubule distribution in growth cones. 1293 42

Panaxynol, a polyacetylene ((3R)-heptadeca-1,9-diene-4,6-diyn-3-ol; syn. falcarinol), was isolated from the lipophilic fractions of Panax notoginseng, a Chinese traditional medicinal plant. In the present study, we reported the neurotrophic effects of panaxynol on PC12D cells and mechanism involved in neurite outgrowth of the cells. Panaxynol could morphologically promote neurite outgrowth in PC12D cells, concentration-dependently reduce cell division and up-regulate molecular marker (MAP1B) expression in PC12D cells. Panaxynol induces the elevation of intracellular cAMP in PC12D cells. The neurite outgrowth in PC12D cells induced by panaxynol could be inhibited by the protein kinase A inhibitor RpcAMPS and by MAP kinase kinase 1/2 inhibitor U0126. These observations reveal that panaxynol could induce the differentiation of PC12D cells in a process similar to but distinct from that of NGF and the panaxynol's effects were via cAMP- and MAP kinase-dependent mechanisms.
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PMID:Panaxynol induces neurite outgrowth in PC12D cells via cAMP- and MAP kinase-dependent mechanisms. 1621 3

The Drosophila homologue of the microtubule associated protein MAP1B is encoded by the futsch locus. The deduced protein Futsch is about twice the size of MAP1B and shows high homology in the N- and C-terminal domains. The central part of Futsch is characterized by a highly repetitive structure based on a 37 amino acid motif. Futsch, like MAP1B, colocalizes with microtubules and is necessary for the organization of the microtubule cytoskeleton during axonal growth and synaptogenesis. To further analyze the functional relevance of Futsch as a MAP1B-like protein, we performed a molecular analysis of the conserved protein domains. Using a number of antisera, we show that, unlike the MAP1B polyprotein, which is cleaved to generate a heavy and light chain, Futsch is expressed as a single protein. The function of MAP1B is in part regulated by phosphorylation mediated by kinases that include casein kinase 2 and glycogen synthase kinase 3beta (GSK3beta). We show here that at least one GSK3beta phosphorylation site of MAP1B is conserved in Futsch and that this site can be phosphorylated by GSK3beta and its Drosophila homologue, Shaggy/Zeste-white 3. To test the functional relevance of these findings we generated a number of minigenes and assayed their ability to rescue the phenotype of futsch mutants. Our data highlight some differences between MAP1B and Futsch but demonstrate that important structural and functional aspects are conserved between fly and vertebrate members of this protein family.
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PMID:The Drosophila microtubule associated protein Futsch is phosphorylated by Shaggy/Zeste-white 3 at an homologous GSK3beta phosphorylation site in MAP1B. 1694 36

DAPK-1 (death-activated protein kinase) has wide ranging functions in cell growth control; however, DAPK-1 interacting proteins that mediate these effects are not well defined. Protein-protein interactions are driven in part by linear interaction motifs, and combinatorial peptide libraries were used to identify peptide interfaces for the kinase domain of DAPK-1. Peptides bound to DAPK-1core kinase domain fragments had homology to the N-terminal domain of the microtubule-associated protein MAP1B. Immunobinding assays demonstrated that DAPK-1 can bind to the full-length human MAP1B, a smaller N-terminal miniprotein containing amino acids 1-126 and the 12-amino acid polypeptides acquired by peptide selection. Amino acid starvation of cells induced a stable immune complex between MAP1B and DAPK-1, identifying a signal that forms the endogenous complex in cells. DAPK-1 and MAP1B co-expression form a synthetic lethal interaction as they cooperate to induce growth inhibition in a clonogenic assay. In cells, two co-localizing populations of DAPK-1 and MAP1B were observed using confocal microscopy; one pool co-localized with MAP1B plus tubulin, and a second pool co-localized with MAP1B plus cortical F-actin. Reduction of MAP1B protein using short interfering RNA attenuated DAPK-1-stimulated autophagy. Transfected MAP1B can synergize with DAPK-1 to stimulate membrane blebbing, whereas reduction of MAP1B using short interfering RNA attenuates DAPK-1 membrane blebbing activity. The autophagy inhibitor 3-methyladenine inhibits the DAPK-1 plus MAP1B-mediated membrane blebbing. These data highlight the utility of peptide aptamers to identify novel binding interfaces and highlight a role for MAP1B in DAPK-1-dependent signaling in autophagy and membrane blebbing.
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PMID:DAPK-1 binding to a linear peptide motif in MAP1B stimulates autophagy and membrane blebbing. 1819 17

The microtubule-associated protein MAP1B has important roles in neural development, particularly in migrating and differentiating neurons. MAP1B is phosphorylated by glycogen synthase kinase 3beta (GSK-3beta) at a site that requires prior phosphorylation by another kinase four amino acid residues downstream of the GSK-3beta site, a so-called primed site, and at non-primed sites that have no such requirement. In developing mammalian neurons, MAP1B phosphorylated by GSK-3beta at primed and non-primed sites is distributed in spatially distinct patterns. Non-primed GSK-3beta-phosphorylated MAP1B sites are only expressed in axons and are present in the form of a gradient that is highest distally, towards the growth cone. In contrast, primed GSK-3beta-phosphorylated MAP1B sites are present throughout the neuron including the somato-dendritic compartment and uniformly throughout the axon. To examine the function of these two sites, we explored the evolutionary conservation of the spatial distribution of GSK-3beta primed and non-primed sites on MAP1B in vertebrate neurons. We immunostained spinal cord sections from embryonic or newly hatched representatives of all of the main vertebrate groups using phospho-specific antibodies to GSK-3beta primed and non-primed sites on MAP1B. This revealed a remarkable evolutionary conservation of the distribution of primed and non-primed GSK-3beta-phosphorylated MAP1B sites in developing vertebrate neurons. By analysing amino acid sequences of MAP1B we found that non-primed GSK-3beta sites are more highly conserved than primed sites throughout the vertebrates, suggesting that the latter evolved later. Finally, distinct distribution patterns of GSK-3beta primed and non-primed sites on MAP1B were preserved in cultured rat embryonic cortical neurons, opening up the possibility of studying the two sites in vitro.
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PMID:Evolution of the spatial distribution of MAP1B phosphorylation sites in vertebrate neurons. 2040 8


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