Cbl: many adaptations to regulate protein tyrosine kinases

Thien, Christine B.F.; Langdon, Wallace Y.

doi:10.1038/35067100

Cited by 585 publications

(550 citation statements)

References 106 publications

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“…The rapid removal of growth factor receptors from the cell surface, and subsequent targeting to lysosomal degradative compartments, provides a down-regulation mechanism important for preventing sustained activation of signaling pathways, which could potentially lead to cellular transformation (reviewed in Marmor and Yarden, 2004). Receptor downregulation is dependent on RTK activation and ubiquitination (Katzmann et al, 2001;Buchberger, 2002;Davies et al, 2004) by the Cbl family of ubiquitin ligases (Joazeiro et al, 1999;Yokouchi et al, 1999;Keane et al, 1999;Thien and Langdon, 2001).…”

Section: Regulation Of Met Downregulation: Consequence For Oncogenic mentioning

confidence: 99%

“…The recruitment of the Cbl family of ubiquitin-protein ligases is required for ligand-induced degradation of many RTKs, among them the epidermal growth factor receptor (EGFR), the platelet-derived growth factor receptor, the colony-stimulating factor-1 receptor (CSF-1R) (reviewed by Thien and Langdon, 2001) and the Met receptor (Peschard et al, 2001Abella et al, 2005) (Figure 3). Growing evidence indicates that ubiquitination of RTKs is critical for their lysosomal degradation, through their ubiquitin-dependent targeting to intralumenal vesicles of MVBs and lysosomal degradation (Urbe et al, 2000;Raiborg et al, 2002;Duan et al, 2003;Jiang et al, 2003;Yamasaki et al, 2003).…”

Section: Regulation Of Met Downregulation: Consequence For Oncogenic mentioning

confidence: 99%

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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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Section: Regulation Of Met Downregulation: Consequence For Oncogenic mentioning

confidence: 99%

Section: Regulation Of Met Downregulation: Consequence For Oncogenic mentioning

confidence: 99%

From Tpr-Met to Met, tumorigenesis and tubes

2007

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“…The domain structure of c-Cbl consists of a tyrosine kinase binding (TKB) domain through which it binds tyrosinephosphorylated targets, a RING finger domain, which binds E2-conjugating enzymes, and a C-terminal ubiquitin-associated (UBA) domain. Additional studies demonstrated that c-Cbl facilitates ligand-induced ubiquitylation of the EGFR [11,12], as well as several other RTKs (reviewed in [13]) by means of RING finger-dependant recruitment of E2 ubiquitin-conjugating enzymes to the receptor's vicinity. Receptor ubiquitylation results in accelerated removal from the cell surface and to subsequent receptor degradation in the lysosomal compartment, thereby terminating RTK signaling.…”

Section: Regulation Of Receptor Endocytosismentioning

confidence: 99%

Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation

2005

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Intracellular signals mediated by the family of receptor tyrosine kinases play pivotal roles in morphogenesis, cell fate determination and pathogenesis. Precise control of signal amplitude and duration is critical for the fidelity and robustness of these processes. Activation of receptor tyrosine kinases by their cognate growth factors not only leads to propagation of the signal through various biochemical cascades, but also sets in motion multiple attenuation mechanisms that ultimately terminate the active state. Early attenuators pre-exist prior to receptor activation and they act to limit signal propagation. Subsequently, late attenuators, such as Lrig and Sprouty, are transcriptionally induced and further act to dampen the signal. Central to the process of signaling attenuation is the role of the E3 ubiquitin ligase c-Cbl. While Cblmediated processes of receptor ubiquitylation and endocytosis are relatively well understood, the links of Cbl to other negative regulators are just now beginning to be appreciated. Here we review some emerging interfaces between Cbl and the transcriptionally induced negative regulators Lrig and Sprouty.

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“…The carboxylterminal of CBL interacts with various SH2 and SH3 domaincontaining proteins. 11 Given CBL's role as an adaptor of various signaling molecules, it is significant that we identified Smad3 as a CBL-interacting protein to suppress TGF-b tumor suppressor pathway.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 Casitas B-lineage lymphoma (CBL) gene encodes for the proteins involved in many cellular processes such as E3 ubiquitin ligase and adaptor. 10,11 Among three homologs of the CBL protein family, CBL (also known as c-CBL) and CBL-b are ubiquitously expressed and have similar functions. 12 They commonly contain tyrosine-kinase-binding domain and a RING finger type (RF) domain that has E3 ubiquitin ligase activity.…”

Section: Introductionmentioning

confidence: 99%

CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-β signaling

et al. 2012

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Casitas B-lineage lymphoma (CBL) protein family functions as multifunctional adaptor proteins and E3 ubiquitin ligases that are implicated as regulators of signaling in various cell types. Recent discovery revealed mutations of proto-oncogenic CBL in the linker region and RING finger domain in human acute myeloid neoplasm, and these transforming mutations induced carcinogenesis. However, the adaptor function of CBL mediated signaling pathway during tumorigenesis has not been well characterized. Here, we show that CBL is highly expressed in breast cancer cells and significantly inhibits transforming growth factor-b (TGF-b) tumor suppressive activity. Knockdown of CBL expression resulted in the increased expression of TGF-b target genes, PAI-I and CDK inhibitors such as p15 INK4b and p21 Cip1 . Furthermore, we demonstrate that CBL is frequently overexpressed in human breast cancer tissues, and the loss of CBL decreases the tumorigenic activity of breast cancer cells in vivo. CBL directly binds to Smad3 through its proline-rich motif, thereby preventing Smad3 from interacting with Smad4 and blocking nuclear translocation of Smad3. CBL-b, one of CBL protein family, also interacted with Smad3 and knockdown of both CBL and CBL-b further enhanced TGF-b transcriptional activity. Our findings provide evidence for a previously undescribed mechanism by which oncogenic CBL can block TGF-b tumor suppressor activity.

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Cbl: many adaptations to regulate protein tyrosine kinases

Cited by 585 publications

References 106 publications

From Tpr-Met to Met, tumorigenesis and tubes

From Tpr-Met to Met, tumorigenesis and tubes

Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation

CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-β signaling

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