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Retrograde neurotrophic signaling requires a protein interacting with receptor tyrosine kinases via C2H2 zinc fingers.

Fu X, Zang K, Zhou Z, Reichardt LF, Xu B - Mol. Biol. Cell (2009)

Bottom Line: Here we show that a novel Trk-interacting protein, NTRAP (neurotrophic factor receptor-associated protein), plays a crucial role in this signaling process.In compartmentalized sensory neuron cultures, down-regulation of NTRAP abolishes the ability of neurotrophins applied to distal axons to activate the transcription factor adenosine 3',5'-monophosphate response element-binding protein (CREB) and to promote neuronal survival.We propose that NTRAP regulates retrograde neurotrophic signaling by controlling the formation of signaling endosomes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Georgetown University, Washington, DC 20057, USA.

ABSTRACT
Neurotrophins at axonal terminals signal to cell bodies to regulate neuronal development via signaling endosomes containing activated Trk receptor tyrosine kinases and mitogen-activated protein kinases (MAPKs). Requirements for the formation of signaling endosomes remain, however, poorly characterized. Here we show that a novel Trk-interacting protein, NTRAP (neurotrophic factor receptor-associated protein), plays a crucial role in this signaling process. NTRAP interacts with the Trk intracellular domain through its C(2)H(2) zinc fingers in a kinase-dependent manner. It is associated with vesicles, some of which contain markers for signaling endosomes. Inhibition of NTRAP function suppresses neurotrophin-induced neurite outgrowth in PC12 cells by altering TrkA endocytic traffic, inhibiting the formation of endosomes containing persistently active MAPKs. In compartmentalized sensory neuron cultures, down-regulation of NTRAP abolishes the ability of neurotrophins applied to distal axons to activate the transcription factor adenosine 3',5'-monophosphate response element-binding protein (CREB) and to promote neuronal survival. We propose that NTRAP regulates retrograde neurotrophic signaling by controlling the formation of signaling endosomes.

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Colocalization of NTRAP with Trk receptors in DRG neurons. Sections at 10 μm were obtained from dissected rat DRG at E18.5 and stained with the affinity-purified NTRAP antibody and an antibody that recognizes all three Trk receptors (A–C). The arrow indicates one neuron that expresses NTRAP but few Trk receptors. The boxed areas are shown in A1–C1 at higher magnification. Scale bars, 5 μm.
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Figure 2: Colocalization of NTRAP with Trk receptors in DRG neurons. Sections at 10 μm were obtained from dissected rat DRG at E18.5 and stained with the affinity-purified NTRAP antibody and an antibody that recognizes all three Trk receptors (A–C). The arrow indicates one neuron that expresses NTRAP but few Trk receptors. The boxed areas are shown in A1–C1 at higher magnification. Scale bars, 5 μm.

Mentions: We used an antibody that recognizes all three Trk receptors for examining colocalization of NTRAP with Trk receptors in individual cells. In E18.5 rat DRG, all Trk-expressing neurons also expressed NTRAP (Figure 2, A–C). Nevertheless, a small number of DRG neurons expressed NTRAP but little Trk. This result is consistent with the observation that TrkA is down-regulated in nonpeptidergic Ret-expressing nociceptors during late embryogenesis and postnatally (Luo et al., 2007). Within the DRG neurons expressing both NTRAP and Trks, the majority of Trks (72 ± 3%, n = 56 neurons) were colocalized with NTRAP (Figure 2, A1–C1).


Retrograde neurotrophic signaling requires a protein interacting with receptor tyrosine kinases via C2H2 zinc fingers.

Fu X, Zang K, Zhou Z, Reichardt LF, Xu B - Mol. Biol. Cell (2009)

Colocalization of NTRAP with Trk receptors in DRG neurons. Sections at 10 μm were obtained from dissected rat DRG at E18.5 and stained with the affinity-purified NTRAP antibody and an antibody that recognizes all three Trk receptors (A–C). The arrow indicates one neuron that expresses NTRAP but few Trk receptors. The boxed areas are shown in A1–C1 at higher magnification. Scale bars, 5 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2801717&req=5

Figure 2: Colocalization of NTRAP with Trk receptors in DRG neurons. Sections at 10 μm were obtained from dissected rat DRG at E18.5 and stained with the affinity-purified NTRAP antibody and an antibody that recognizes all three Trk receptors (A–C). The arrow indicates one neuron that expresses NTRAP but few Trk receptors. The boxed areas are shown in A1–C1 at higher magnification. Scale bars, 5 μm.
Mentions: We used an antibody that recognizes all three Trk receptors for examining colocalization of NTRAP with Trk receptors in individual cells. In E18.5 rat DRG, all Trk-expressing neurons also expressed NTRAP (Figure 2, A–C). Nevertheless, a small number of DRG neurons expressed NTRAP but little Trk. This result is consistent with the observation that TrkA is down-regulated in nonpeptidergic Ret-expressing nociceptors during late embryogenesis and postnatally (Luo et al., 2007). Within the DRG neurons expressing both NTRAP and Trks, the majority of Trks (72 ± 3%, n = 56 neurons) were colocalized with NTRAP (Figure 2, A1–C1).

Bottom Line: Here we show that a novel Trk-interacting protein, NTRAP (neurotrophic factor receptor-associated protein), plays a crucial role in this signaling process.In compartmentalized sensory neuron cultures, down-regulation of NTRAP abolishes the ability of neurotrophins applied to distal axons to activate the transcription factor adenosine 3',5'-monophosphate response element-binding protein (CREB) and to promote neuronal survival.We propose that NTRAP regulates retrograde neurotrophic signaling by controlling the formation of signaling endosomes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Georgetown University, Washington, DC 20057, USA.

ABSTRACT
Neurotrophins at axonal terminals signal to cell bodies to regulate neuronal development via signaling endosomes containing activated Trk receptor tyrosine kinases and mitogen-activated protein kinases (MAPKs). Requirements for the formation of signaling endosomes remain, however, poorly characterized. Here we show that a novel Trk-interacting protein, NTRAP (neurotrophic factor receptor-associated protein), plays a crucial role in this signaling process. NTRAP interacts with the Trk intracellular domain through its C(2)H(2) zinc fingers in a kinase-dependent manner. It is associated with vesicles, some of which contain markers for signaling endosomes. Inhibition of NTRAP function suppresses neurotrophin-induced neurite outgrowth in PC12 cells by altering TrkA endocytic traffic, inhibiting the formation of endosomes containing persistently active MAPKs. In compartmentalized sensory neuron cultures, down-regulation of NTRAP abolishes the ability of neurotrophins applied to distal axons to activate the transcription factor adenosine 3',5'-monophosphate response element-binding protein (CREB) and to promote neuronal survival. We propose that NTRAP regulates retrograde neurotrophic signaling by controlling the formation of signaling endosomes.

Show MeSH
Related in: MedlinePlus