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Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance.

Meriane M, Tcherkezian J, Webber CA, Danek EI, Triki I, McFarlane S, Bloch-Gallego E, Lamarche-Vane N - J. Cell Biol. (2004)

Bottom Line: Fyn, but not Src, is able to phosphorylate the intracellular domain of DCC in vitro, and we demonstrate that Y1418 is crucial for DCC axon outgrowth function.Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants.We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, H3A 2B2, Canada.

ABSTRACT
Netrin-1 acts as a chemoattractant molecule to guide commissural neurons (CN) toward the floor plate by interacting with the receptor deleted in colorectal cancer (DCC). The molecular mechanisms underlying Netrin-1-DCC signaling are still poorly characterized. Here, we show that DCC is phosphorylated in vivo on tyrosine residues in response to Netrin-1 stimulation of CN and that the Src family kinase inhibitors PP2 and SU6656 block both Netrin-1-dependent phosphorylation of DCC and axon outgrowth. PP2 also blocks the reorientation of Xenopus laevis retinal ganglion cells that occurs in response to Netrin-1, which suggests an essential role of the Src kinases in Netrin-1-dependent orientation. Fyn, but not Src, is able to phosphorylate the intracellular domain of DCC in vitro, and we demonstrate that Y1418 is crucial for DCC axon outgrowth function. Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1.

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The model. Netrin-1 binding to DCC induces a rapid phosphorylation of Y1418 in the vicinity of the P3 region by Fyn. This primary event might initiate directly or indirectly the activation of a specific unknown guanine nucleotide exchange factor (GEF) that activates Rac1, leading subsequently to actin assembly at the plasma membrane, axon outgrowth, and attraction.
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fig9: The model. Netrin-1 binding to DCC induces a rapid phosphorylation of Y1418 in the vicinity of the P3 region by Fyn. This primary event might initiate directly or indirectly the activation of a specific unknown guanine nucleotide exchange factor (GEF) that activates Rac1, leading subsequently to actin assembly at the plasma membrane, axon outgrowth, and attraction.

Mentions: We provide the first evidence that the transmembrane receptor DCC is regulated by phosphorylation in a Netrin-1–dependent manner. In dissociated CN, DCC is highly phosphorylated on serine, threonine, and tyrosine residues in response to Netrin-1. Fyn tyrosine kinase regulates DCC phosphorylation and is required to mediate axon outgrowth and attraction induced by Netrin-1. In vitro studies suggest that Y1418 in the vicinity of the P3 region of the intracellular tail of DCC is a likely phosphorylation site for Fyn, but not Src, tyrosine kinase. Phosphorylation of this tyrosine residue is essential for DCC to promote neurite outgrowth in N1E-115 cells and to mediate downstream signals leading to the activation of the small GTPase Rac1 (Fig. 9).


Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance.

Meriane M, Tcherkezian J, Webber CA, Danek EI, Triki I, McFarlane S, Bloch-Gallego E, Lamarche-Vane N - J. Cell Biol. (2004)

The model. Netrin-1 binding to DCC induces a rapid phosphorylation of Y1418 in the vicinity of the P3 region by Fyn. This primary event might initiate directly or indirectly the activation of a specific unknown guanine nucleotide exchange factor (GEF) that activates Rac1, leading subsequently to actin assembly at the plasma membrane, axon outgrowth, and attraction.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172574&req=5

fig9: The model. Netrin-1 binding to DCC induces a rapid phosphorylation of Y1418 in the vicinity of the P3 region by Fyn. This primary event might initiate directly or indirectly the activation of a specific unknown guanine nucleotide exchange factor (GEF) that activates Rac1, leading subsequently to actin assembly at the plasma membrane, axon outgrowth, and attraction.
Mentions: We provide the first evidence that the transmembrane receptor DCC is regulated by phosphorylation in a Netrin-1–dependent manner. In dissociated CN, DCC is highly phosphorylated on serine, threonine, and tyrosine residues in response to Netrin-1. Fyn tyrosine kinase regulates DCC phosphorylation and is required to mediate axon outgrowth and attraction induced by Netrin-1. In vitro studies suggest that Y1418 in the vicinity of the P3 region of the intracellular tail of DCC is a likely phosphorylation site for Fyn, but not Src, tyrosine kinase. Phosphorylation of this tyrosine residue is essential for DCC to promote neurite outgrowth in N1E-115 cells and to mediate downstream signals leading to the activation of the small GTPase Rac1 (Fig. 9).

Bottom Line: Fyn, but not Src, is able to phosphorylate the intracellular domain of DCC in vitro, and we demonstrate that Y1418 is crucial for DCC axon outgrowth function.Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants.We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, H3A 2B2, Canada.

ABSTRACT
Netrin-1 acts as a chemoattractant molecule to guide commissural neurons (CN) toward the floor plate by interacting with the receptor deleted in colorectal cancer (DCC). The molecular mechanisms underlying Netrin-1-DCC signaling are still poorly characterized. Here, we show that DCC is phosphorylated in vivo on tyrosine residues in response to Netrin-1 stimulation of CN and that the Src family kinase inhibitors PP2 and SU6656 block both Netrin-1-dependent phosphorylation of DCC and axon outgrowth. PP2 also blocks the reorientation of Xenopus laevis retinal ganglion cells that occurs in response to Netrin-1, which suggests an essential role of the Src kinases in Netrin-1-dependent orientation. Fyn, but not Src, is able to phosphorylate the intracellular domain of DCC in vitro, and we demonstrate that Y1418 is crucial for DCC axon outgrowth function. Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1.

Show MeSH
Related in: MedlinePlus