Binding of Cbl to a Phospholipase Cγ1-docking Site on Platelet-derived Growth Factor Receptor β Provides a Dual Mechanism of Negative Regulation

Reddi, Alagarsamy Lakku; Guo, Ying; Duan, Lei; Chen, Gengsheng; Dimri, Manjari; Douillard, Patrice; Druker, Brian J.; Naramura, Mayumi; Band, Vimla

doi:10.1074/jbc.m701797200

Cited by 35 publications

(30 citation statements)

References 65 publications

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“…We found that cells, both normal human fibroblasts (AG1523) and glioblastoma cells (U251MG) lacking c-Cbl and Cbl-b had a stronger chemotactic response toward PDGF compared with control cells, partially consistent with a previous study where a similar effect was seen by cells lacking only c-Cbl (5). Previous studies have shown that the effect of c-Cbl overexpression on PDGF-induced proliferation depends on the passage number of the clone (4), suggesting that the cell adapts to continued c-Cbl overexpression.…”

Section: Discussionsupporting

confidence: 78%

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The Ubiquitin Ligases c-Cbl and Cbl-b Negatively Regulate Platelet-derived Growth Factor (PDGF) BB-induced Chemotaxis by Affecting PDGF Receptor β (PDGFRβ) Internalization and Signaling

Rorsman

Tsioumpekou

Heldin

et al. 2016

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 78%

“…c-Cbl overexpression has been shown to lead to enhanced PDGFR␣ and ␤ ubiquitination and degradation as well as reduced PDGF-dependent proliferation and survival (4,5). The Cbl family consists of c-Cbl, Cbl-b, and Cbl-c (6).…”

mentioning

confidence: 99%

The Ubiquitin Ligases c-Cbl and Cbl-b Negatively Regulate Platelet-derived Growth Factor (PDGF) BB-induced Chemotaxis by Affecting PDGF Receptor β (PDGFRβ) Internalization and Signaling

Rorsman

Tsioumpekou

Heldin

et al. 2016

Journal of Biological Chemistry

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“…The E3 ubiquitin ligase, c-Cbl, is activated after PDGF stimulation and associates with phosphorylated PDGFR␤ (21,22). This in turn leads to PDGFR␤ ubiquitination, internalization via the clathrin-mediated pathway, and lysosomal degradation negatively regulating PDGFR␤ signaling and cell proliferation (21).…”

Section: Discussionmentioning

confidence: 99%

Endothelial and Smooth Muscle-derived Neuropilin-like Protein Regulates Platelet-derived Growth Factor Signaling in Human Vascular Smooth Muscle Cells by Modulating Receptor Ubiquitination

Guo

Nie

Esmailzadeh

et al. 2009

Journal of Biological Chemistry

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Endothelial and smooth muscle cell-derived neuropilin-like protein (ESDN) is up-regulated in the neointima of remodeling arteries and modulates vascular smooth muscle cell (VSMC) growth. Platelet-derived growth factor (PDGF) is the prototypic growth factor for VSMCs and plays a key role in vascular remodeling. Here, we sought to further define ESDN function in primary human VSMCs. ESDN down-regulation by RNA interference significantly enhanced PDGF-induced VSMC DNA synthesis and migration. This was associated with increased ERK1/2, Src, and PDGF receptor (PDGFR)␤ phosphorylation, without altering total PDGFR␤ expression levels. In binding assays, ESDN down-regulation significantly increased 125 I-PDGF maximum binding (B max ) to PDGF receptors on VSMCs without altering the binding constant (K d ), raising the possibility that ESDN regulates PDGFR processing. ESDN down-regulation significantly reduced ligand-induced PDGFR␤ ubiquitination. This was associated with a significant reduction in the expression level of c-Cbl, an E3 ubiquitin ligase that ubiquitinylates PDGFR␤. Thus, ESDN modulates PDGF signaling in VSMCs via regulation of PDGFR surface levels. The ESDN effect is mediated, at least in part, through effects on PDGFR␤ ubiquitination. ESDN may serve as a target for regulating PDGFR␤ signaling in VSMCs.Vascular injury initiates a cascade of events that ultimately leads to vascular remodeling and often intimal hyperplasia. Vascular smooth muscle cell (VSMC) 2 proliferation and migration are key cellular events in this process. Platelet-derived growth factor (PDGF)-BB is released by platelets, endothelial cells, VSMCs, and inflammatory cells at the sites of vascular injury and is a particularly potent regulator of VSMC proliferation and migration (1). PDGF binding to PDGF receptor (PDGFR)␤ in VSMCs leads to receptor dimerization, autophosphorylation, and activation of downstream signaling pathways, including MAPK. The ligand-bound receptor is internalized through the endocytotic pathway and may either recycle to the membrane or undergo ubiquitination and lysosomal degradation (2). A number of endogenous stimulatory and inhibitory regulators, including the E3 ubiquitin ligase, c-Cbl (3), tightly regulate the mitogenic stimulus by modulating the duration and intensity of the signal.We have identified endothelial and smooth muscle cell-derived neuropilin-like protein (ESDN, also called CLCP1 or DCBLD2) as a marker and regulator of cell proliferation in vascular remodeling (4). ESDN is a transmembrane protein with a domain structure similar to neuropilins (5, 6). ESDN can be induced by PDGF-BB and serum and is highly expressed in the neointima of injured rat (5), mouse (4), and human (4) arteries. ESDN expression parallels cell proliferation in the vessel wall in vivo (4). Furthermore, ESDN is up-regulated in proliferating VSMCs, and ESDN overexpression inhibits VSMC growth (4). Here, we expand the scope of our previous studies to demonstrate that ESDN regulates PDGF-induced VSMC migration and inhibits PDGF signa...

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“…However, our data suggest that in contrast with F-actin assembly, c-Cbl does not mediate SLAP mitogenic inhibition. Therefore, c-Cbl may use distinct mechanisms for PDGFR association and ubiquitination (Reddi et al, 2007). Thus, we propose that SLAP dictates c-Cblspecificity towards PDGFR signalling.…”

Section: Slap Associates With C-cbl and Affects Rac Activationmentioning

confidence: 99%

The Src-like adaptor protein regulates PDGF-induced actin dorsal ruffles in a c-Cbl-dependent manner

et al. 2008

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The Src-like adaptor protein (SLAP) belongs to the subfamily of adapter proteins that negatively regulate cellular signalling initiated by tyrosine kinases. SLAP has a unique, myristylated N-terminus, followed by SH3 and SH2 domains with high homology to Src family tyrosine kinases (SFK) and a unique C-terminal tail, which is important for c-Cbl binding. We have previously shown that SLAP negatively regulates platelet-derived growth factor (PDGF)-induced mitogenesis in fibroblasts and we now report that it regulates F-actin assembly for dorsal ruffles formation. c-Cbl mediated SLAP inhibition towards actin remodelling. Moreover, SLAP enhanced PDGF-induced c-Cbl phosphorylation by SFK. In contrast, SLAP mitogenic inhibition was not mediated by c-Cbl, but it rather involved a competitive mechanism with SFK for PDGF-receptor (PDGFR) association and mitogenic signalling. Accordingly, phosphorylation of the Src mitogenic substrates Stat3 and Shc were reduced by SLAP. Thus, we concluded that SLAP regulates PDGFR signalling by two independent mechanisms: a competitive mechanism for PDGF-induced Src mitogenic signalling and a non-competitive mechanism for dorsal ruffles formation mediated by c-Cbl.

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Binding of Cbl to a Phospholipase Cγ1-docking Site on Platelet-derived Growth Factor Receptor β Provides a Dual Mechanism of Negative Regulation

Abstract: Ubiquitin conjugation to receptor tyrosine kinases is a critical

Cited by 35 publications

References 65 publications

The Ubiquitin Ligases c-Cbl and Cbl-b Negatively Regulate Platelet-derived Growth Factor (PDGF) BB-induced Chemotaxis by Affecting PDGF Receptor β (PDGFRβ) Internalization and Signaling

The Ubiquitin Ligases c-Cbl and Cbl-b Negatively Regulate Platelet-derived Growth Factor (PDGF) BB-induced Chemotaxis by Affecting PDGF Receptor β (PDGFRβ) Internalization and Signaling

Endothelial and Smooth Muscle-derived Neuropilin-like Protein Regulates Platelet-derived Growth Factor Signaling in Human Vascular Smooth Muscle Cells by Modulating Receptor Ubiquitination

The Src-like adaptor protein regulates PDGF-induced actin dorsal ruffles in a c-Cbl-dependent manner

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