Protein kinase C and F‐actin are essential for stimulation of neuronal FAK tyrosine phosphorylation by G‐proteins and amyloid beta protein

Zhang, Chi; Qiu, Haoqun; Krafft, Grant A.; Klein, William L.

doi:10.1016/0014-5793(96)00435-8

Cited by 45 publications

(26 citation statements)

References 19 publications

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“…As mentioned above, several studies have indicated that effects of A␤ on cells, including neurotoxicity, are dependent upon an intact microfilament network (Furukawa and Zhang et al, 1996b). We therefore tested whether the A␤-induced cytoskeletal accumulation of paxillin described above is similarly actin-dependent.…”

Section: A␤-induced Cytoskeletal Paxillin Accumulation Is Actin-depenmentioning

confidence: 93%

“…Prior to harvesting the cells after the 3 hr incubation at 37°C, the control vs. cytochalasin D-treated cells could not be distinguished morphologically, indicating minimal disruption of cellular integrity during the incubation (not shown). This experiment demonstrates that A␤-induced paxillin translocation, like A␤-induced cytotoxicity (Furukawa and Mattson, 1995) and FAK tyrosine phosphorylation (Zhang et al, 1996b), is dependent upon an intact microfilament network.…”

Section: A␤-induced Cytoskeletal Paxillin Accumulation Is Actin-depenmentioning

confidence: 97%

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Rapid impact of ?-amyloid on Paxillin in a neural cell line

1997

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Beta-amyloid1-42 (Abeta) is a naturally occuring peptide whose accumulation in the brain is putatively coupled to Alzheimer's disease pathogenesis. Deleterious effects of Abeta on neurons have been linked to the inappropriate activation of signaling pathways within the cell (reviewed in Yankner, 1996), including tyrosine phosphorylation of focal adhesion kinase (FAK) (Zhang et al., 1994, 1996a,b). Here we have investigated the effects of Abeta on paxillin in a neural cell line. Paxillin, a substrate for FAK, is thought to act as a signal "integrator," functioning to link other proteins into multi-molecular signaling complexes (reviewed in Turner, 1994). Treatment of the rat central nervous system B103 cell line with aggregates of Abeta was found to induce the tyrosine phosphorylation of paxillin within 30 min, nearly 24 hr prior to significant cell death. Particularly striking was a subsequent "mobilization" of paxillin to the cytoskeleton in Abeta-treated cells. The amount of paxillin associated with the cytoskeleton in Abeta-treated cells was increased 10-fold over controls. The Abeta-induced paxillin accumulation could be visualized immunocytochemically, with an increase in number and size of paxillin-labeled focal contacts upon treatment with Abeta. This effect was specific, in that vinculin, another focal contact protein, was unaffected by Abeta. Disruption of f-actin, which inhibits both Abeta-induced neurotoxicity (Furukawa and Mattson, 1995) and focal contact signaling in B103 cells (Zhang et al., 1996b) was found to block the cytoskeletal paxillin accumulation. The rapid tyrosine phosphorylation and cytoskeletal mobilization of paxillin links Abeta to the activation of focal contact signaling events that may influence neuronal cytoskeletal architecture, gene expression, synaptic plasticity and cell viability.

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Section: A␤-induced Cytoskeletal Paxillin Accumulation Is Actin-depenmentioning

confidence: 93%

Section: A␤-induced Cytoskeletal Paxillin Accumulation Is Actin-depenmentioning

confidence: 97%

Rapid impact of ?-amyloid on Paxillin in a neural cell line

1997

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“…Previous studies in nonneuronal cells have shown that both Ca 2ϩ and ROS are relevant to signaling via Src family protein tyrosine kinases (59)(60)(61). In neuronal cells, toxicity of traditional A␤ preparations also has been linked to transduction molecules associated with focal contact signaling (32,62,63), a cascade that includes Fyn (41). In B103 cells, ADDLs have been found to stimulate Fyn kinase Ϸ2-fold within 30 min (C.Z.…”

Section: Discussionmentioning

confidence: 99%

Diffusible, nonfibrillar ligands derived from Aβ _1–42 are potent central nervous system neurotoxins

Lambert

Barlow

Chromy

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

3,288

142

3,008

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A␤ 1-42 is a self-associating peptide whose neurotoxic derivatives are thought to play a role in Alzheimer's pathogenesis. Neurotoxicity of amyloid ␤ protein (A␤) has been attributed to its fibrillar forms, but experiments presented here characterize neurotoxins that assemble when fibril formation is inhibited. These neurotoxins comprise small diffusible A␤ oligomers (referred to as ADDLs, for A␤-derived diffusible ligands), which were found to kill mature neurons in organotypic central nervous system cultures at nanomolar concentrations. At cell surfaces, ADDLs bound to trypsin-sensitive sites and surface-derived tryptic peptides blocked binding and afforded neuroprotection. Germ-line knockout of Fyn, a protein tyrosine kinase linked to apoptosis and elevated in Alzheimer's disease, also was neuroprotective. Remarkably, neurological dysfunction evoked by ADDLs occurred well in advance of cellular degeneration. Without lag, and despite retention of evoked action potentials, ADDLs inhibited hippocampal long-term potentiation, indicating an immediate impact on signal transduction. We hypothesize that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer's disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of A␤-derived diffusible ligands acting upon particular neural signal transduction pathways.

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“…Furthermore, PKC activation induces phosphorylation of focal adhesion kinase (FAK), a protein involved in integrin-mediated cytoskeletal changes. This enhancement of FAK activity was dependent on intact F-actin (Zhang et al, 1996). Thus, PKC can be both activated by matrix and also influence cell/matrix interactions by inside-out signaling to integrins through FAK.…”

Section: Discussionmentioning

confidence: 89%

Protein kinase C mediates neurite guidance at an astrocyte boundary

Powell

Mercado

Calle

et al. 2001

Glia

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Protein kinase C and F‐actin are essential for stimulation of neuronal FAK tyrosine phosphorylation by G‐proteins and amyloid beta protein

Cited by 45 publications

References 19 publications

Rapid impact of ?-amyloid on Paxillin in a neural cell line

Rapid impact of ?-amyloid on Paxillin in a neural cell line

Diffusible, nonfibrillar ligands derived from Aβ _1–42 are potent central nervous system neurotoxins

Protein kinase C mediates neurite guidance at an astrocyte boundary

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Protein kinase C and F‐actin are essential for stimulation of neuronal FAK tyrosine phosphorylation by G‐proteins and amyloid beta protein

Cited by 45 publications

References 19 publications

Rapid impact of ?-amyloid on Paxillin in a neural cell line

Rapid impact of ?-amyloid on Paxillin in a neural cell line

Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins

Protein kinase C mediates neurite guidance at an astrocyte boundary

Contact Info

Product

Resources

About

Diffusible, nonfibrillar ligands derived from Aβ _1–42 are potent central nervous system neurotoxins