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Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced
Y Zhang1, D B Moheban, B R Conway
1Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
Internalization and transport of a ligand-receptor complex are required to initiate cell body responses to target-derived neurotrophin. However, it is not known whether internalized receptors and cell surface receptors initiate the same signaling pathways and biological responses. Here we use a temperature-sensitive mutant of dynamin (G273D) to control the subcellular localization of activated NGF receptors (Trks). We show that dynamin function is required for ligand-dependent endocytosis of Trk receptors. In PC12 cells, nerve growth factor (NGF) stimulation promotes both survival and neuronal differentiation. These distinct biological responses to NGF are controlled by receptors signaling from different locations within the cell. Neuronal differentiation is promoted by catalytically active Trks within endosomes in the cell interior. In contrast, survival responses are initiated by activated receptors at the cell surface where they orchestrate prolonged activation of the kinase Akt. Thus, interactions between Trk receptor tyrosine kinases and intracellular signaling molecules are dictated both by phosphotyrosine motifs within the receptors and by the intracellular location of phosphorylated receptors.
Insights
Nerve growth factor (NGF) receptors signal from different cellular locations to trigger distinct responses. Internalized receptors promote neuronal differentiation, while surface receptors drive cell survival via Akt activation.
Area of Science:
- Cell biology
- Neuroscience
- Molecular signaling
Background:
- Ligand-receptor complex internalization is crucial for cellular responses to neurotrophins.
- The distinct signaling pathways and biological outcomes initiated by cell surface versus internalized receptors remain unclear.
Purpose of the Study:
- To investigate the role of dynamin in the subcellular localization of activated NGF receptors (Trks).
- To determine whether NGF receptors signaling from different cellular compartments elicit distinct biological responses.
Main Methods:
- Utilized a temperature-sensitive dynamin mutant (G273D) to control Trk receptor localization.
- Stimulated PC12 cells with NGF and analyzed receptor endocytosis and downstream signaling.
Main Results:
- Dynamin function is essential for ligand-dependent endocytosis of Trk receptors.
- NGF stimulation in PC12 cells induces both survival and neuronal differentiation.
- Neuronal differentiation is mediated by active Trks within intracellular endosomes.
- Cell survival is initiated by activated Trks at the cell surface, leading to sustained Akt activation.
Conclusions:
- Distinct biological responses to NGF are regulated by Trk receptor signaling from different subcellular locations.
- The intracellular localization of phosphorylated Trk receptors dictates their interactions with signaling molecules and downstream effects.