Activated Cdc42 Sequesters c-Cbl and Prevents EGF Receptor Degradation

Wu, Wen Jin; Tu, S. Sean; Cerione, Richard A.

doi:10.1016/s0092-8674(03)00688-3

Cited by 188 publications

(178 citation statements)

References 33 publications

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“…However, only when Cdc42 disengages from the ACK2/SH3PX1 complex, presumably because of GTP hydrolysis, would ACK2/SH3PX1 associate with clathrin, which may be necessary to ensure that these sorting participants are properly conveyed to the endosomes. It is interesting that we have also found that Cdc42 regulates the Cbl-catalyzed ubiquitination of EGF receptors (18), which has been shown to be essential for receptor degradation (42,43). Taken together, these results have led us to propose that the EGF-dependent activation of Cdc42 provides a timing mechanism for the sorting and degradation of EGF receptors.…”

Section: Discussionmentioning

confidence: 76%

“…It will be interesting in the future to better understand exactly how Cdc42 activation is maintained for Binding of EGF to the EGF receptor promotes the activation of the Src tyrosine kinase that phosphorylates (P*) and stimulates the GEF activity of Vav2. This in turn leads to the activation of Cdc42, which enables it to engage targets at the plasma membrane like ACK2 and WASP, as well as regulate Cbl through the binding of activated Cdc42 to the Cool-1 (for cloned-out-of-library)/␤-Pix (for PAK-interactive exchange factor) protein (18). The EGF-and Srcdependent phosphorylation of Cdc42 promotes its binding to RhoGDI.…”

Section: Discussionmentioning

confidence: 99%

“…Activated (GTP-bound) Cdc42 negatively regulates the binding of ACK/ SH3PX1 to clathrin (16) and thus may serve to set the timing for EGF receptor sorting. Likewise, recently we have found that activated forms of Cdc42 block the binding of the Cbl ubiquitin ligase to EGF receptors, thereby providing a mechanism for regulating the timing of receptor ubiquitination (18).…”

mentioning

confidence: 96%

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Epidermal Growth Factor-dependent Regulation of Cdc42 Is Mediated by the Src Tyrosine Kinase

Wang

et al. 2003

Journal of Biological Chemistry

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102

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Cdc42 is a member of the Rho subfamily of Ras-related GTP-binding proteins and has been implicated in a wide range of cellular processes and signaling activities. Among its best known actions is the regulation of actin cytoskeletal architecture, because microinjection of activated Cdc42 was found to give rise to filopodia formation, whereas the closely related Rac and RhoA proteins were implicated in membrane ruffling and in the generation of actin stress fibers, respectively (1-4). A number of lines of evidence have also implicated Cdc42 in the control of normal cell growth and, when hyperactivated, in cellular transformation. These include the findings that Dbl (for diffuse B cell lymphoma) and a number of related guanine nucleotide exchange factors (GEFs) 1 for Cdc42 and other Rho proteins are capable of transforming cells and that mutations in Cdc42 that mimic the actions of GEFs and allow the spontaneous exchange of GDP for GTP exhibit oncogenic activity (5-10).

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 96%

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Epidermal Growth Factor-dependent Regulation of Cdc42 Is Mediated by the Src Tyrosine Kinase

Wang

et al. 2003

Journal of Biological Chemistry

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102

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“…In a similar manner, the loss of the direct Cbl TKB-binding site in the CSF-1R (Mancini et al, 2002), as well as the loss of Cbl recruitment to the Kit receptor (Herbst et al, 1995), results in enhanced transforming activity. Multiple additional mechanisms that reduce Cbl-mediated ubiquitination of RTKs, such as enhanced Cbl degradation or sequestration, have been identified (Wong et al, 2002;Bao et al, 2003;Wu et al, 2003;Lee et al, 2004). These observations suggest that loss of a Cbl TKB binding site may be a common mechanism that contributes to full oncogenic activation of RTKs.…”

Section: Loss Of Cbl Ubiquitylation In Oncogenic Rtksmentioning

confidence: 97%

From Tpr-Met to Met, tumorigenesis and tubes

2007

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The receptor for hepatocyte growth factor (HGF)/scatter factor (SF), Met, controls a program of invasive epithelial growth through the coordination of cell proliferation and survival, cell migration and epithelial morphogenesis. This process is important during embryogenesis and for organ regeneration in the adult. However, when deregulated the HGF/SF-Met signaling axis contributes to tumorigenesis and metastasis. Studies on the oncogenic activation of the Met receptor have shed light on the molecular mechanisms underlying the oncogenic activation of receptor tyrosine kinase (RTKs). More than a decade ago, work on the Met related oncogene, Tpr-Met, revealed the mechanism for activation of RTK-derived oncogenes generated following chromosomal translocation. More recently, studies on the mechanisms of downregulation of the Met RTK highlight a role for loss of downregulation in RTK oncogenic activation.

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“…New data by Sorkin and coworkers show that EGFR ubiquitination is not required for internalization but plays a role in the targeting of the EGFR to late endosomes and multivesicular bodies for degradation, providing additional mechanistic detail on the role of Cbl in EGFR downregulation (Huang et al, 2007). Interestingly, activated Cdc42 sequesters Cbl away from the EGFR and inhibits its downregulation (Wu et al, 2003). However, there is no evidence linking the effect of activated Cdc42 in EGFR downregulation and signaling in the context of polarized epithelia, and it is not known whether the depolarization of epithelia observed upon expression of activated Cdc42 is related to an increase in EGFR-mediated signaling.…”

Section: How Cancer Hijacks the Epp Machineriesmentioning

confidence: 99%

The epithelial polarity program: machineries involved and their hijacking by cancer

2008

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The Epithelial Polarity Program (EPP) adapts and integrates three ancient cellular machineries to construct an epithelial cell. The polarized trafficking machinery adapts the cytoskeleton and ancestral secretory and endocytic machineries to the task of sorting and delivering different plasma membrane (PM) proteins to apical and basolateral surface domains. The domain-identity machinery builds a tight junctional fence (TJ) between apical and basolateral PM domains and adapts ancient polarity proteins and polarity lipids on the cytoplasmic side of the PM, which have evolved to perform a diversity of polarity tasks across cells and species, to provide 'identity' to each epithelial PM domain. The 3D organization machinery utilizes adhesion molecules as positional sensors of other epithelial cells and the basement membrane and small GTPases as integrators of positional information with the activities of the domain-identity and polarized trafficking machineries. Cancer is a disease mainly of epithelial cells (90% of human cancers are carcinomas that derive from epithelial cells) that hijacks the EPP machineries, resulting in loss of epithelial polarity, which often correlates in extent with the aggressiveness of the tumor. Here, we review how the EPP integrates its three machineries and the strategies used by cancer to hijack them.

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Activated Cdc42 Sequesters c-Cbl and Prevents EGF Receptor Degradation

Cited by 188 publications

References 33 publications

Epidermal Growth Factor-dependent Regulation of Cdc42 Is Mediated by the Src Tyrosine Kinase

Epidermal Growth Factor-dependent Regulation of Cdc42 Is Mediated by the Src Tyrosine Kinase

From Tpr-Met to Met, tumorigenesis and tubes

The epithelial polarity program: machineries involved and their hijacking by cancer

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