Eph receptors inactivate R-Ras through different mechanisms to achieve cell repulsion

Dail, Monique; Richter, Melanie; Godement, Pierre; Pasquale, Elena B.

doi:10.1242/jcs.02842

Cited by 64 publications

(67 citation statements)

References 77 publications

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“…The activity of small GTPases is upregulated by specific guanine nucleotide exchange factors (GEFs) and downregulated by GTPase-activating proteins (GAPs). Several repulsive proteins have been shown to decrease Ras activity by activating specific GAPs, thereby inducing growth cone collapse and neurite retraction (Elowe et al, 2001;Oinuma et al, 2004;Dail et al, 2006). However, the involvement of Ras activity regulation in the RGMa-neogenin signal transduction has not been confirmed.…”

Section: Introductionmentioning

confidence: 99%

Inactivation of Ras by p120GAP via Focal Adhesion Kinase Dephosphorylation Mediates RGMa-Induced Growth Cone Collapse

Endo¹,

Yamashita²

2009

J. Neurosci.

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The repulsive guidance molecule RGMa performs several functions in the developing and adult CNSs. RGMa, through its receptor neogenin, induces growth cone collapse and neurite outgrowth inhibition. Here, we demonstrate that RGMa binding to neogenin leads to the inactivation of Ras, which is required for the RGMa-mediated repulsive function in cortical neurons. This signal transduction is mediated by the Ras-specific GTPase-activating protein (GAP) p120GAP. The SH2 domain of p120GAP interacts with focal adhesion kinase (FAK), which is phosphorylated at Tyr-397. When the cells are stimulated with RGMa, FAK undergoes dephosphorylation at Tyr-397 and is dissociated from p120GAP, and this dissociation is followed by an increase in the interaction between p120GAP and GTP-Ras. In addition, the knockdown of p120GAP prevents RGMa-induced growth cone collapse and neurite outgrowth inhibition. Furthermore, RGMa stimulation induces Akt inactivation through p120GAP, and the expression of the constitutively active Akt prevents RGMa-induced growth cone collapse. Thus, RGMa binding to neogenin regulates p120GAP activity through FAK Tyr-397 dephosphorylation, leading to the inactivation of Ras and its downstream effector Akt, and this signal transduction plays a role in the RGMa-mediated repulsive function.

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Section: Introductionmentioning

confidence: 99%

Inactivation of Ras by p120GAP via Focal Adhesion Kinase Dephosphorylation Mediates RGMa-Induced Growth Cone Collapse

Endo¹,

Yamashita²

2009

J. Neurosci.

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“…In contrast, GTPase-activating proteins (GAPs) accelerate the hydrolysis of GTP to GDP. ␣2-Chimaerin, a GTPase-activating protein for Rac, and p120RasGAP, a GTPase-activating protein for H-Ras and R-Ras, have been recently implicated in EphA-dependent repulsive responses (Dail et al, 2006;Beg et al, 2007;Iwasato et al, 2007;Wegmeyer et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The EphA4 Receptor Regulates Neuronal Morphology through SPAR-Mediated Inactivation of Rap GTPases

Richter

Murai²,

Bourgin³

et al. 2007

J. Neurosci.

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“…Cell rounding in response to ephrin-A treatment was examined by using wild-type and pgsD-677 CHO cells as described in ref. 23. Growth cone collapse in response to ephrin-A treatment was examined by using wild-type and Ext1 null cortical neurons.…”

Section: Methodsmentioning

confidence: 99%

“…Activation of ephrin-A/EphA signaling induces a variety of cellular responses, one of which is retraction of the cell periphery and cell rounding (23,24). Wild-type CHO cells underwent robust cell rounding in response to ephrin-A3 (Fig.…”

Section: Ephrin-a3-induced Cell Rounding Is Impaired In Cho Cells Lacmentioning

confidence: 99%

Heparan sulfate regulates ephrin-A3/EphA receptor signaling

Irie¹,

Okuno²,

Matsumoto³

et al. 2008

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

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Increasing evidence indicates that many signaling pathways involve not only ligands and receptors but also various types of coreceptors and matrix components as additional layers of regulation. Signaling by Eph receptors and their ephrin ligands plays a key role in a variety of biological processes, such as axon guidance and topographic map formation, synaptic plasticity, angiogenesis, and cancer. Little is known about whether the ephrin-Eph receptor signaling system is subject to such additional layers of regulation. Here, we show that ephrin-A3 binds to heparan sulfate, and that the presence of cell surface heparan sulfate is required for the full biological activity of ephrin-A3. Among the ephrins tested, including ephrin-A1, -A2, -A5, -B1, and -B2, only ephrin-A3 binds heparin or heparan sulfate. Ephrin-A3-dependent EphA receptor activation is reduced in mutant cells that are defective in heparan sulfate synthesis, in wild-type cells from which cell surface heparan sulfate has been removed, and in the hippocampus of conditional knockout mice defective in heparan sulfate synthesis. Ephrin-A3-dependent cell rounding is impaired in CHO cells lacking heparan sulfate, and cortical neurons lacking heparan sulfate exhibit impaired growth cone collapse. In contrast, cell rounding and growth cone collapse in response to ephrin-A5, which does not bind heparan sulfate, are not affected by the absence of heparan sulfate. These results show that heparan sulfate modulates ephrin/Eph signaling and suggest a physiological role for heparan sulfate proteoglycans in the regulation of ephrin-A3-dependent biological processes.proteoglycan ͉ cell adhesion ͉ growth cone collapse H eparan sulfate is a class of sulfated glycosaminoglycans. It occurs as heparan sulfate proteoglycans, in which one or more heparan sulfate chains are covalently attached to a variety of core proteins (1). Heparin is a specialized form of heparan sulfate synthesized exclusively by connective tissue mast cells, whereas heparan sulfate is expressed in many cell types. The negatively charged sulfate groups of heparan sulfate mediate interactions with a variety of proteins. Increasing evidence indicates that heparan sulfate acts as an integral component of a number of morphogen and growth factor signaling pathways by interacting with these molecules. For example, fibroblast growth factors, Wnts, Sonic hedgehog, bone morphogenetic proteins, and neuregulins bind to heparan sulfate and are functionally modulated by it (2, 3). Molecules involved in axon pathfinding, such as netrin-1, Slit, and semaphorins, are other major targets of regulation by heparan sulfate (4). We have used genetic ablation of the Ext1 gene, which encodes a glycosyltransferase essential for heparan sulfate synthesis (5, 6), to demonstrate the physiological significance of the interactions of some of these molecules with heparan sulfate (7-9).The Eph receptors form the largest family of receptor tyrosine kinases. Together with their membrane-bound ligands, the ephrins, they are involved in b...

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Eph receptors inactivate R-Ras through different mechanisms to achieve cell repulsion

Cited by 64 publications

References 77 publications

Inactivation of Ras by p120GAP via Focal Adhesion Kinase Dephosphorylation Mediates RGMa-Induced Growth Cone Collapse

Inactivation of Ras by p120GAP via Focal Adhesion Kinase Dephosphorylation Mediates RGMa-Induced Growth Cone Collapse

The EphA4 Receptor Regulates Neuronal Morphology through SPAR-Mediated Inactivation of Rap GTPases

Heparan sulfate regulates ephrin-A3/EphA receptor signaling

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