The adapter protein, Grb10, is a positive regulator of vascular endothelial growth factor signaling

Giorgetti‐Peraldi, Sophie; Murdaca, Joseph; Jl, Mas; Obberghen, E. Van

doi:10.1038/sj.onc.1204520

Cited by 31 publications

(36 citation statements)

References 30 publications

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“…In endothelial (HUVEC) cells VEGF-induction increased transcriptional activation of Grb10. Elevated Grb10 expression further potentiated expression and tyrosine phosphorylation of the VEGFR3 (KDR) following accelerated mitogenic signaling [54]. This effect was mediated by direct association of Grb10 to the activated receptor through the Grb10 SH2 domain.…”

Section: Grb10 In Vegfr Regulationmentioning

confidence: 92%

Grb10 is a dual regulator of receptor tyrosine kinase signaling

Kabir

Kazi

2014

Mol Biol Rep

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Section: Grb10 In Vegfr Regulationmentioning

confidence: 92%

Grb10 is a dual regulator of receptor tyrosine kinase signaling

Kabir

Kazi

2014

Mol Biol Rep

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“…We have shown that the adaptor molecule Grb10 is involved in a positive feedback loop in VEGF signaling. VEGF stimulates Grb10 mRNA expression in human umbilical vein endothelial cells (HUVEC), and in turn, ectopic expression of Grb10 induces an increase in the amount and the tyrosine phosphorylation of VEGF-R2 in HUVEC and in HEK-293 cells (7). Our hypothesis was that Grb10 inhibited VEGF-R2 degradation.…”

Section: Vascular Endothelial Growth Factor (Vegf)mentioning

confidence: 98%

Grb10 Prevents Nedd4-mediated Vascular Endothelial Growth Factor Receptor-2 Degradation

Murdaca

Treins

Monthouël-Kartmann

et al. 2004

Journal of Biological Chemistry

124

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One of the cellular mechanisms used to prevent continuous and enhanced activation in response to growth factors is the internalization and degradation of their receptors. Little is known about the molecular mechanisms involved in vascular endothelial growth factor receptor-2 (VEGF-R2) degradation. In a previous work, we have shown that the adaptor protein Grb10 is a positive regulator of the VEGF signaling pathway. Indeed, VEGF stimulates Grb10 expression, and Grb10 overexpression induces an increase in the amount and the tyrosine phosphorylation of VEGF-R2. In the present manuscript, we demonstrate that Grb10 stimulates VEGF-R2 expression by inhibiting the Nedd4-mediated VEGF-R2 degradation. First, we show that proteasome inhibition by MG132 induces an increase in VEGF-R2 amount, and that VEGF-R2 is ubiquitinated in response to VEGF. Expression of Nedd4, a HECT domain-containing ubiquitin ligase, induces the disappearance of VEGF-R2 in cells, suggesting that Nedd4 is involved in VEGF-R2 degradation. To determine whether Nedd4 directly ubiquitinates VEGF-R2, we expressed a ubiquitin ligase-deficient mutant Nedd4C854S. In the presence of Nedd4C854S, VEGF-R2 is expressed and ubiquitinated. These results suggest that VEGF-R2 is ubiquitinated but that Nedd4 is not involved in this process. Finally, we show that Grb10 constitutively associates with Nedd4.

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“…The SH2 domain is critical for the role of Grb10 in the mitogen-activated protein kinase (MAPK) pathway, having direct interactions with numerous critical components including MEK1 and RAF1 (11). The SH2 domain also interacts with many receptor proteins implicated in cell proliferation, differentiation, and control of the cell cycle, including RET, KIT, MET, PDGFR, EGFR, FLT3, and VEGFR-2 (9,(12)(13)(14)(15)(16). Additionally, the SH2 domain has been implicated in Grb10 homodimerization, which is hypothesized to enable Grb10 to integrate signals from multiple pathways through the formation of larger protein complexes (17).…”

Section: Grb10 Binding Partners Define Its Role In Developmentmentioning

confidence: 99%

Tissue-specific regulation and function of Grb10 during growth and neuronal commitment

Plasschaert

Bartolomei

2014

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

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Growth-factor receptor bound protein 10 (Grb10) is a signal adapter protein encoded by an imprinted gene that has roles in growth control, cellular proliferation, and insulin signaling. Additionally, Grb10 is critical for the normal behavior of the adult mouse. These functions are paralleled by Grb10’s unique tissue-specific imprinted expression; the paternal copy of Grb10 is expressed in a subset of neurons whereas the maternal copy is expressed in most other adult tissues in the mouse. The mechanism that underlies this switch between maternal and paternal expression is still unclear, as is the role for paternally expressed Grb10 in neurons. Here, we review recent work and present complementary data that contribute to the understanding of Grb10 gene regulation and function, with specific emphasis on growth and neuronal development. Additionally, we show that in vitro differentiation of mouse embryonic stem cells into alpha motor neurons recapitulates the switch from maternal to paternal expression observed during neuronal development in vivo. We postulate that this switch in allele-specific expression is related to the functional role of Grb10 in motor neurons and other neuronal tissues.

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The adapter protein, Grb10, is a positive regulator of vascular endothelial growth factor signaling

Cited by 31 publications

References 30 publications

Grb10 is a dual regulator of receptor tyrosine kinase signaling

Grb10 is a dual regulator of receptor tyrosine kinase signaling

Grb10 Prevents Nedd4-mediated Vascular Endothelial Growth Factor Receptor-2 Degradation

Tissue-specific regulation and function of Grb10 during growth and neuronal commitment

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