NGF Signals through TrkA to Increase Clathrin at the Plasma Membrane and Enhance Clathrin-Mediated Membrane Trafficking

Beattie, Eric C.; Howe, Charles L.; Wilde, Andrew; Brodsky, Frances M.; Mobley, William C.

doi:10.1523/jneurosci.20-19-07325.2000

Cited by 121 publications

(96 citation statements)

References 48 publications

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“…To address the possibility that TrkA was internalized in the differentiated PC12 cells, we analyzed the relative level of TrkA on the cell surface of the differentiated PC12 cells. Consistent with reports demonstrating that receptor activation triggers internalization (31,32), cell surface biotinylation experiments showed that TrkA rapidly leaves the surface of naive PC12 cells upon NGF stimulation. After 7 days of continual NGF treatment, we could not detect TrkA among the streptavidin-precipitated cell surface proteins (Fig.…”

Section: Figsupporting

confidence: 88%

Persistent TrkA Activity Is Necessary to Maintain Transcription in Neuronally Differentiated PC12 Cells

Chang

Mellon

Schanen

et al. 2003

Journal of Biological Chemistry

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Neurotrophins are required for the differentiation and survival of several different neuronal subpopulations in the developing nervous system. The PC12 cell line responds to nerve growth factor (NGF) by withdrawing from the cell cycle and acquiring a sympathetic neuronlike phenotype. Previous studies have shown that the activation kinetics of the NGF receptor, TrkA, and downstream protein kinases appear rapid and seemingly transient after NGF treatment of naive PC12 cells. However, maintenance of the neuronal phenotype and survival of differentiated PC12 cells under serum-free conditions require constant NGF exposure. In this study we have addressed the mechanisms that NGF uses to maintain neuronal PC12 cells. We show that TrkA remains phosphorylated at a basal level throughout differentiation of the PC12 cells. The phospho-TrkA levels in the differentiated PC12 cells were diminished by both complete NGF withdrawal and pharmacological inhibition of Trk kinase activity. Intracellular sequestration of the majority of TrkA molecules (both phosphorylated and nonphosphorylated TrkA) and persistent dephosphorylation of the small pool of cell surface TrkA renders the persistent phospho-TrkA signal in the differentiated PC12 cells resistant to partial NGF withdrawal as well as exposure to additional NGF. NGF regulated both extracellular-regulated kinases 1/2 and Akt activity in the differentiated PC12 cells via sustained TrkA activity. Moreover, analysis of transcription using activating protein 1-, serum response element-, and cyclic AMP response element-Luc reporter constructs showed that NGF regulated these promoters through TrkA activity in differentiated PC12 cells. Interestingly, the initial response of the cyclic AMP response element promoter to NGF was delayed, becoming Trk-dependent well beyond the peaks in TrkA and downstream protein kinase signal transduction.During development, nerve growth factor (NGF) 1 has profound effects on the differentiation and survival of subsets of neurons in the peripheral and central nervous systems (1). These effects are largely mediated through activation of the TrkA receptor, which initiates a cascade of signaling events that includes activation of several downstream protein kinases and transcription factors (2). These early events are thought to generate the long term changes in gene expression needed for acquisition of a mature neuronal phenotype. Mature or adult neurons are also exposed to and responsive to neurotrophins like NGF, but their biological responses may be quite distinct from those of an immature neuron. For example, developing nociceptive neurons in the dorsal root ganglion require NGF for survival (3). NGF alters neurite outgrowth, gene induction, and the responsiveness of adult nociceptive neurons to some stimuli, but it is apparently not necessary for their survival (4 -6). Much effort has been devoted toward understanding how NGF and other neurotrophins bring about their biological effects in both the developing and adult nervous systems. Most studies of ne...

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Section: Figsupporting

confidence: 88%

Persistent TrkA Activity Is Necessary to Maintain Transcription in Neuronally Differentiated PC12 Cells

Chang

Mellon

Schanen

et al. 2003

Journal of Biological Chemistry

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“…The binding of EGF to its receptor causes phosphorylation of the clathrin heavy chain and a global redistribution of clathrin to the cell periphery [42]. The majority of newly induced CCPs do not actually colocalize with the NGF receptors [43,44]. This is distinct from our observation of de novo formation of CCPs specifically around bound virus particles without a global redistribution of clathrin [29].…”

Section: Dynamics Of Influenza Endocytosiscontrasting

confidence: 79%

Endocytosis of influenza viruses

Lakadamyali

Rust

Zhuang

2004

Microbes and Infection

305

267

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Receptor-mediated endocytosis is known to play an important role in the entry of many viruses into host cells. However, the exact internalization mechanism has, until recently, remained poorly understood for many medically important viruses, including influenza. Developments in real-time imaging of single viruses as well as the use of dominant negative mutants to selectively block specific endocytic pathways, have improved our understanding of the influenza infection process.

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“…There, the binding of EGF to its receptor causes phosphorylation of the clathrin heavy chain and a global redistribution of clathrin to the cell periphery to form CCPs 44 . The majority of newly induced CCPs do not actually colocalize with the NGF receptors 45,46 . This is distinct from our observations of de novo formation of CCPs at the virus binding sites without a global redistribution of clathrin upon viral binding.…”

Section: Discussionmentioning

confidence: 94%

Assembly of endocytic machinery around individual influenza viruses during viral entry

Rust

Lakadamyali

Zhang

et al. 2004

Nat Struct Mol Biol

417

433

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Most viruses enter cells via receptor-mediated endocytosis. However, the entry mechanisms used by many of them remain unclear. How viruses are targeted to cellular endocytic machinery is also largely unknown. We have studied the entry mechanisms of influenza viruses by tracking the interaction of single viruses with cellular endocytic structures in real time using fluorescence microscopy. Our results show that influenza can exploit clathrin-mediated and clathrin-and caveolin-independent endocytic pathways in parallel, both pathways leading to viral fusion with similar efficiency. Remarkably, viruses taking the clathrin-mediated pathway enter cells via the de novo formation of clathrin-coated pits (CCPs) at viral binding sites. CCP formation at these sites is much faster than elsewhere on the cell surface, suggesting a virus-induced CCP formation mechanism that may be commonly exploited by many other types of viruses.

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NGF Signals through TrkA to Increase Clathrin at the Plasma Membrane and Enhance Clathrin-Mediated Membrane Trafficking

Cited by 121 publications

References 48 publications

Persistent TrkA Activity Is Necessary to Maintain Transcription in Neuronally Differentiated PC12 Cells

Persistent TrkA Activity Is Necessary to Maintain Transcription in Neuronally Differentiated PC12 Cells

Endocytosis of influenza viruses

Assembly of endocytic machinery around individual influenza viruses during viral entry

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