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

Rubin, Chanan; Gur, Gal; Yarden, Yosef

doi:10.1038/sj.cr.7290268

Cited by 82 publications

(74 citation statements)

References 56 publications

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“…The basal levels of cytokine receptors are thought to be maintained through the balance between synthesis, delivery, retention, and degradation [45]. The accumulating evidence shows that besides the well-characterized ligand-induced pathways, there are ligand-independent pathways of receptor degradation.…”

Section: Discussionmentioning

confidence: 99%

E3 ligase FLRF (Rnf41) regulates differentiation of hematopoietic progenitors by governing steady-state levels of cytokine and retinoic acid receptors

Jing

Infante

Nachtman

et al. 2008

Experimental Hematology

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Objective-FLRF (Rnf41) gene was identified through screening of subtracted cDNA libraries form murine hematopoietic stem cells and progenitors. Subsequent work has revealed that FLRF acts as E3 ubiquitin ligase, and that it regulates steady-state levels of neuregulin receptor ErbB3, and participates in degradation of IAP protein BRUCE and parkin. The objective of this study was to start exploring the role of FLRF during hematopoiesis.Methods-FLRF was over-expressed in a murine multipotent hematopoietic progenitor cell line EML, which can differentiate into almost all blood cell lineages, and in pro-B progenitor cell line BaF3. The impact of FLRF over-expression on EML cell differentiation into myelo-erythroid lineages was studied using hematopoietic colony-forming assays. The interaction of FLRF with cytokine receptors and receptor levels in control cells and EML and BaF3 cells over-expressing FLRF were examined with Western and immunoprecipitation.Results-Remarkably, over-expression of FLRF significantly attenuated erythroid and myeloid differentiation of EML cells in response to cytokines Epo and IL-3, and retinoic acid (RA), and resulted in significant and constitutive decrease of steady-state levels of IL-3, Epo and RA receptor RARα in EML and BaF3 cells. Immunoprecipitation has revealed that FLRF interacts with IL-3, Epo and RARα receptors in EML and BaF3 cells, and that FLRF-mediated down-regulation of these receptors is ligand binding-independent.Conclusions-The results of this study have revealed new FLRF-mediated pathway for ligandindependent receptor level regulation, and support the notion that through maintaining basal levels of cytokine receptors, FLRF is involved in the control of hematopoietic progenitor cell differentiation into myelo-erythroid lineages.

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Section: Discussionmentioning

confidence: 99%

E3 ligase FLRF (Rnf41) regulates differentiation of hematopoietic progenitors by governing steady-state levels of cytokine and retinoic acid receptors

Jing

Infante

Nachtman

et al. 2008

Experimental Hematology

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“…Another mechanism for attenuating TIE2 activation is the induction of its turnover in a dose-dependent manner by ANGPT1 and, less intensely, by ANGPT2, leading to the ubiquitination and degradation of the receptor (30). The amplitude and length of the signaling over tyrosine kinase receptors such as TIE2 seem to have a critical role in such a mechanism of attenuation (31). The high levels of ANGPT expression, associated with the chronic nature of BA, may explain the negative correlation between ANGPT1 and ANGPT2 and their receptor TIE2 in the affected patients.…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin 1 and angiopoietin 2 are associated with medial thickening of hepatic arterial branches in biliary atresia

et al. 2013

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Background: Biliary atresia (BA) is an infantile disorder characterized by progressive sclerosing cholangiopathy leading to biliary obstruction. First-line treatment of BA is hepatoportoenterostomy, the prognosis of which is related to age at surgery and to histological variables such as extent of fibrosis and ductular reaction. Hepatic arterial medial thickening (MT) suggests an arteriopathy in BA pathogenesis. We evaluated the expression of angiopoietin (ANGPT)/tyrosine kinase with immunoglobulin-like and epidermal growth factorlike domains 2 (TIE2) system in liver samples obtained from patients with BA, correlating it with MT, variables associated with disease severity, and postoperative prognosis. Methods: ANGPT1, ANGPT2, and TIE2 expression levels were assessed by quantitative PCR in liver samples obtained from BA patients (n = 23) at portoenterostomy and age-matched infants with intrahepatic cholestasis (IHC; n = 7). Histological variables were morphometrically assessed. results: ANGPT1 and ANGPT2 were overexpressed in BA in comparison with IHC (P = 0.024 and P = 0.029, respectively). In BA, ANGPTs expression was positively correlated with MT (ANGPT1: r s = 0.59, P = 0.013; ANGPT2: r s = 0.52, P = 0.032), not with the variables associated with disease severity. TIE2 and ANGPTs expression levels were negatively correlated (ANGPT1: r s = −0.73, P < 0.001; ANGPT2: r s = −0.54, P = 0.007). conclusion: In BA, there is overexpression of both ANGPT1 and ANGPT2, which is correlated with MT but not with age at portoenterostomy or with the histological variables associated with disease severity at the time of procedure. Biliary atresia (BA) is an infantile hepatobiliary disorder characterized by the obstruction of bile ducts associated with a progressive sclerosing cholangiopathy. The primary treatment for BA is a hepatoportoenterostomy, which should be performed as soon as possible, because its chances of longterm success decrease when the age at surgery increases (1). In addition to age at portoenterostomy, histological findings observed in biopsies collected at the time of the procedure, such as the extents of fibrosis and ductular reaction, represent variables associated with disease severity and can help foresee the postoperative outcomes (2).Regardless of portoenterostomy, BA induces cirrhosis by the continuous sclerosing cholangiopathy process, thus making this entity the leading cause of liver transplantation in children.The etiology of such a cholangiopathy remains elusive, and BA seems to represent more a phenotype than a unique disease. Our group is interested in the putative role of an arteriopathy in the development of BA because there are arteriographic (3), ultrasonographic (4-6), computed tomographic (7), histological (8), and immunohistochemical (9) evidences of medial thickening (MT) in hepatic artery branches owing to a vascular remodeling associated with hypoxia-ischemia in the portal tracts and porta hepatis. Knowledge on the behavior of angiogenic molecules in the liver of the affected patients...

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“…For instance, macrophages obtained from mice lacking Cbl, a ubiquitin ligase that targets Fms to the endocytic machinery, 32,33 exhibited a delayed downregulation of Fms, a prolonged tyrosine phosphorylation of Fms and downstream molecules, and an enhanced growth response to M-CSF. [34][35][36] In this , c and 6), but those signals were terminated more quickly due to the rapid Fms downregulation (Figure 5b).…”

Section: Discussionmentioning

confidence: 99%

IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation

et al. 2010

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Macrophage colony-stimulating factor (M-CSF) regulates the production, survival and function of macrophages through Fms, the receptor tyrosine kinase. Recently, interleukin-34 (IL-34), which shares no sequence homology with M-CSF, was identified as an alternative Fms ligand. Here, we provide the first evidence that these ligands indeed resemble but are not necessarily identical in biological activity and signal activation. In culture systems tested, IL-34 and M-CSF showed an equivalent ability to support cell growth or survival. However, they were different in the ability to induce the production of chemokines such as MCP-1 and eotaxin-2 in primary macrophages, the morphological change in TF-1-fms cells and the migration of J774A.1 cells. Importantly, IL-34 induced a stronger but transient tyrosine phosphorylation of Fms and downstream molecules, and rapidly downregulated Fms. Even in the comparison of active domains, these ligands showed no sequence homology including the position of cysteines. Interestingly, an anti-Fms monoclonal antibody (Mab) blocked both IL-34-Fms and M-CSF-Fms binding, but another MAb blocked only M-CSF-Fms binding. These results suggested that IL-34 and M-CSF differed in their structure and Fms domains that they bound, which caused different bioactivities and signal activation kinetics/strength. Our findings indicate that macrophage phenotype and function are differentially regulated even at the level of the single receptor, Fms.

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

Cited by 82 publications

References 56 publications

E3 ligase FLRF (Rnf41) regulates differentiation of hematopoietic progenitors by governing steady-state levels of cytokine and retinoic acid receptors

E3 ligase FLRF (Rnf41) regulates differentiation of hematopoietic progenitors by governing steady-state levels of cytokine and retinoic acid receptors

Angiopoietin 1 and angiopoietin 2 are associated with medial thickening of hepatic arterial branches in biliary atresia

IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation

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