cAMP-dependent protein kinase A is required for Schwann cell growth: Interactions between the cAMP and neuregulin/tyrosine kinase pathways

Kim, Haesun A.; DeClue, Jeffrey E.; Ratner, Nancy

doi:10.1002/(sici)1097-4547(19970715)49:2<236::aid-jnr12>3.0.co;2-z

Cited by 107 publications

(79 citation statements)

References 72 publications

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“…PKA plays a key role in the signaling cascades triggered by receptors activating adenyl cyclase directly but is also involved, via Ca 2ϩ -stimulated adenyl cyclases, in pathways employing Ca 2ϩ as a second messenger (56). PKA phosphorylates Tau and MAP2c directly but also activates downstream kinases able to phosphorylate residues not targeted by PKA (57)(58)(59)(60). The effects of direct phosphorylation by PKA addressed in this study differ not only between Tau and MAP2 isoforms but also between different activities of the MAPs.…”

Section: Phosphorylation Of Map2c and Interaction With 14-3-3mentioning

confidence: 81%

Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau

Jansen

Melková

Trošanová

et al. 2017

Journal of Biological Chemistry

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Edited by Norma AllewellMicrotubule-associated protein 2c (MAP2c) is involved in neuronal development and is less characterized than its homolog Tau, which has various roles in neurodegeneration. Using NMR methods providing single-residue resolution and quantitative comparison, we investigated molecular interactions important for the regulatory roles of MAP2c in microtubule dynamics. We found that MAP2c and Tau significantly differ in the position and kinetics of sites that are phosphorylated by cAMP-dependent protein kinase (PKA), even in highly homologous regions. We determined the binding sites of unphosphorylated and phosphorylated MAP2c responsible for interactions with the regulatory protein 14-3-3 . Differences in phosphorylation and in charge distribution between MAP2c and Tau suggested that both MAP2c and Tau respond to the same signal (phosphorylation by PKA) but have different downstream effects, indicating a signaling branch point for controlling microtubule stability. Although the interactions of phosphorylated Tau with 14-3-3 are supposed to be a major factor in microtubule destabilization, the binding of 14-3-3 to MAP2c enhanced by PKA-mediated phosphorylation is likely to influence microtubule-MAP2c binding much less, in agreement with the results of our tubulin co-sedimentation measurements. The specific location of the major MAP2c phosphorylation site in a region homologous to the muscarinic receptor-binding site of Tau suggests that MAP2c also may regulate processes other than microtubule dynamics.Cytoskeletal microtubule-associated proteins (MAPs) 3 are proteins of critical importance for regulating the stability and dynamics of microtubules (1). MAP2 and Tau represent MAP subfamilies expressed in neurons; MAP2 is localized in dendrites, whereas Tau is found mainly in axons (2). Tau and MAP2 belong to the class of intrinsically disordered proteins (IDPs), which lack a unique structure and which exist in multiple, quickly interconverting conformations (3-7). NMR is the method of choice for structural investigation of this type of protein. Tau and MAP2 differ in their N-terminal projection domains, which contain acidic and proline-rich subdomains, whereas the C-terminal parts, containing the microtubulebinding domain (MTBD) and the C-terminal region, are homologous (8). Tau is expressed in several splice variants. The human brain isoforms differ in the number of microtubulebinding regions (MTBRs) in the C-terminal portion and in the presence of two inserts near the N terminus. For the sake of simplicity, only the 441-residue variant lacking exons 6, 8, and 10 (9) is discussed in this paper. This variant has been studied in detail and was shown to form paired helical filaments and neurofibillary tangles in brains of patients suffering from Alzheimer's disease (10). The MAP2 family is composed of two high-molecular-weight proteins, MAP2a and MAP2b, each consisting of 1830 amino acids, and two low-molecular-weight proteins, MAP2c and MAP2d, consisting of 467 and 498 amino acids, respectively. The ...

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Section: Phosphorylation Of Map2c and Interaction With 14-3-3mentioning

confidence: 81%

Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau

Jansen

Melková

Trošanová

et al. 2017

Journal of Biological Chemistry

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“…Increasing cAMP alone, in the absence of serum or exogenous growth factors, does not increase proliferation but induces markers of differentiation, e.g., P0 (Morgan et al, 1991). However, when cAMP is elevated in concert with exposure to serum or growth factors, such as neuregulin, then a synergistic effect is seen and there is robust cell proliferation (Lemke and Brockes, 1984;Stewart et al, 1991;Kim et al, 1997;Rahmatullah et al, 1998;Monje et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase A-Induced Phosphorylation of the p65 Subunit of Nuclear Factor-κB Promotes Schwann Cell Differentiation into a Myelinating Phenotype

Yoon

Korade²,

Carter

2008

J. Neurosci.

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Axon-Schwann cell interactions are critical for myelin formation during peripheral nerve development and regeneration. Axonal contact promotes Schwann cell precursors to differentiate into a myelinating phenotype, and cAMP-elevating agents can mimic this; however, the mechanisms underlying this differentiation are poorly understood. We demonstrated previously that the transcription factor nuclear factor-B (NF-B) is required for myelin formation by Schwann cells (Nickols et al., 2003), although how it is activated during this process remained to be determined. Here, we report that culturing Schwann cells with sensory neurons results in the activation of cAMPdependent protein kinase (PKA), and this kinase phosphorylates the p65 subunit of NF-B at S276. The phosphorylation was also induced in cultured Schwann cells by treatment with forskolin, dibutyryl-cAMP, or by overexpression of a catalytic subunit of PKA, and this increased the transcriptional activity of NF-B. In developing perinatal rat sciatic nerve, the kinetics of p65 phosphorylation at S276 paralleled that of PKA and NF-B activation. To elucidate the role of p65 phosphorylation in myelin formation, we overexpressed an S276A mutant of p65 in cultured Schwann cells, which blocked PKA-mediated transcriptional activation of NF-B. When the Schwann cells expressing the mutant were cocultured with sensory neurons, there was a 45% reduction in the number of myelinated fibers relative to controls, demonstrating a requirement for p65 phosphorylation by PKA during myelin formation.

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“…Growth factors such as PDGF and neuregulins signal through the Ras/Raf/MAPK pathway to regulate cell-cycle progression in SCs (Kim et al, 1997a;Kim et al, 2001b;Maurel and Salzer, 2000), but the effect of adenosine on ERK/MAPK signaling in SCs has not been explored previously.…”

Section: Adenosine Is An Activity-dependent Signal Activating Erk/mapmentioning

confidence: 99%

“…Activation of ERK/MAPK underlies the mitogenic effects of many growth factors, but ERK can also mediate cell-cycle arrest (Pumiglia and Decker, 1997). In SCs, the ERK/ MAPK cascade represents a point of cross-talk between growth factors and cAMP signaling pathways, whereby cAMP can either enhance or inhibit growth-factor mediated ERK signaling (and cell-cycle progression) (Kim et al, 1997a;Kim et al, 1997b;Kim et al, 2001a). This might help explain our present findings that acute activation of A2 adenosine receptors strongly activated ERK/MAPK in SCs, but inhibited growth factor-induced stimulation of SC proliferation.…”

Section: Adenosine Is a Candidate Axon-derived Signal Elevating Intramentioning

confidence: 99%

Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells

et al. 2004

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Nonsynaptic release of ATP from electrically stimulated dorsal root gangion (DRG) axons inhibits Schwann cell (SC) proliferation and arrests SC development at the premyelinating stage, but the specific types of purinergic receptor(s) and intracellular signaling pathways involved in this form of neuron-glia communication are not known. Recent research shows that adenosine is a neuron-glial transmitter between axons and myelinating glia of the CNS. The present study investigates the possibility that adenosine might have a similar function in communicating between axons and premyelinating SCs. Using a combination of pharmacological and molecular approaches, we found that mouse SCs in culture express functional adenosine receptors and ATP receptors, a far more complex array of purinergic receptors than thought previously. Adenosine, but not ATP, activates ERK/MAPK through stimulation of cAMP-linked A2 A adenosine receptors. Both ATP and adenosine inhibit proliferation of SCs induced by platelet-derived growth factor (PDGF), via mechanisms that are partly independent. In contrast to ATP, adenosine failed to inhibit the differentiation of SCs to the O4+ stage. This indicates that, in addition to ATP, adenosine is an activity-dependent signaling molecule between axons and premyelinating Schwann cells, but that electrical activity, acting through adenosine, has opposite effects on the differentiation of myelinating glia in the PNS and CNS.

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cAMP-dependent protein kinase A is required for Schwann cell growth: Interactions between the cAMP and neuregulin/tyrosine kinase pathways

Cited by 107 publications

References 72 publications

Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau

Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau

Protein Kinase A-Induced Phosphorylation of the p65 Subunit of Nuclear Factor-κB Promotes Schwann Cell Differentiation into a Myelinating Phenotype

Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells

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