Publications by authors named "Yonathan Lissanu Deribe"

17 Publications

  • Page 1 of 1

Sequential Administration of XPO1 and ATR Inhibitors Enhances Therapeutic Response in TP53-mutated Colorectal Cancer.

Gastroenterology 2021 Mar 19. Epub 2021 Mar 19.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background & Aims: Understanding the mechanisms by which tumors adapt to therapy is critical for developing effective combination therapeutic approaches to improve clinical outcomes for patients with cancer.

Methods: To identify promising and clinically actionable targets for managing colorectal cancer (CRC), we conducted a patient-centered functional genomics platform that includes approximately 200 genes and paired this with a high-throughput drug screen that includes 262 compounds in four patient-derived xenografts (PDXs) from patients with CRC.

Results: Both screening methods identified exportin 1 (XPO1) inhibitors as drivers of DNA damage-induced lethality in CRC. Molecular characterization of the cellular response to XPO1 inhibition uncovered an adaptive mechanism that limited the duration of response in TP53-mutated, but not in TP53-wild-type CRC models. Comprehensive proteomic and transcriptomic characterization revealed that the ATM/ATR-CHK1/2 axes were selectively engaged in TP53-mutant CRC cells upon XPO1 inhibitor treatment and that this response was required for adapting to therapy and escaping cell death. Administration of KPT-8602, an XPO1 inhibitor, followed by AZD-6738, an ATR inhibitor, resulted in dramatic antitumor effects and prolonged survival in TP53-mutant models of CRC.

Conclusions: Our findings anticipate tremendous therapeutic benefit and support the further evaluation of XPO1 inhibitors, especially in combination with DNA damage checkpoint inhibitors, to elicit an enduring clinical response in patients with CRC harboring TP53 mutations.
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http://dx.doi.org/10.1053/j.gastro.2021.03.022DOI Listing
March 2021

Loss of ARID1A Promotes Epithelial-Mesenchymal Transition and Sensitizes Pancreatic Tumors to Proteotoxic Stress.

Cancer Res 2021 01 6;81(2):332-343. Epub 2020 Nov 6.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Cellular dedifferentiation is a key mechanism driving cancer progression. Acquisition of mesenchymal features has been associated with drug resistance, poor prognosis, and disease relapse in many tumor types. Therefore, successful targeting of tumors harboring these characteristics is a priority in oncology practice. The SWItch/Sucrose non-fermentable (SWI/SNF) chromatin remodeling complex has also emerged as a critical player in tumor progression, leading to the identification of several SWI/SNF complex genes as potential disease biomarkers and targets of anticancer therapies. AT-rich interaction domain-containing protein 1A (ARID1A) is a component of SWI/SNF, and mutations in represent one of the most frequent molecular alterations in human cancers. mutations occur in approximately 10% of pancreatic ductal adenocarcinomas (PDAC), but whether these mutations confer a therapeutic opportunity remains unclear. Here, we demonstrate that loss of ARID1A promotes an epithelial-mesenchymal transition (EMT) phenotype and sensitizes PDAC cells to a clinical inhibitor of HSP90, NVP-AUY922, both and . Although loss of ARID1A alone did not significantly affect proliferative potential or rate of apoptosis, ARID1A-deficient cells were sensitized to HSP90 inhibition, potentially by promoting the degradation of intermediate filaments driving EMT, resulting in cell death. Our results describe a mechanistic link between ARID1A defects and a quasi-mesenchymal phenotype, suggesting that deleterious mutations in associated with protein loss exhibit potential as a biomarker for patients with PDAC who may benefit by HSP90-targeting drugs treatment. SIGNIFICANCE: This study identifies ARID1A loss as a promising biomarker for the identification of PDAC tumors that are potentially responsive to treatment with proteotoxic agents.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3922DOI Listing
January 2021

Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure.

Nat Genet 2020 11 5;52(11):1178-1188. Epub 2020 Oct 5.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Somatic mutations in driver genes may ultimately lead to the development of cancer. Understanding how somatic mutations accumulate in cancer genomes and the underlying factors that generate somatic mutations is therefore crucial for developing novel therapeutic strategies. To understand the interplay between spatial genome organization and specific mutational processes, we studied 3,000 tumor-normal-pair whole-genome datasets from 42 different human cancer types. Our analyses reveal that the change in somatic mutational load in cancer genomes is co-localized with topologically-associating-domain boundaries. Domain boundaries constitute a better proxy to track mutational load change than replication timing measurements. We show that different mutational processes lead to distinct somatic mutation distributions where certain processes generate mutations in active domains, and others generate mutations in inactive domains. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation-rate variations observed in human cancers.
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http://dx.doi.org/10.1038/s41588-020-0708-0DOI Listing
November 2020

Telomere dysfunction activates YAP1 to drive tissue inflammation.

Nat Commun 2020 09 21;11(1):4766. Epub 2020 Sep 21.

Department of Pathology, Texas Children's Hospital, Houston, TX, 77030, USA.

Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.
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http://dx.doi.org/10.1038/s41467-020-18420-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505960PMC
September 2020

Author Correction: Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer.

Nat Med 2018 Oct;24(10):1627

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

In the version of this article originally published, information regarding several funding sources was omitted from the Acknowledgements section. The following sentences should have been included: "This work was supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program, the UT Lung SPORE 5 P50 CA07090, and the MD Anderson Cancer Center Support Grant P30CA01667. V.P is supported by R01CA155196-01A1 from the National Cancer Institute." Also, reference 18 was incorrect. The original reference was: Kim, E. S. et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 1, 44-53 (2011). It should have been: Papadimitrakopoulou, V. et al. The BATTLE-2 study: a biomarker-integrated targeted therapy study in previously treated patients with advanced non-small-cell lung cancer. J Clin. Oncol. 34, 3638-3647 (2016). The errors have been corrected in the HTML and PDF versions of this article.
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http://dx.doi.org/10.1038/s41591-018-0173-9DOI Listing
October 2018

Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer.

Nat Med 2018 07 11;24(7):1047-1057. Epub 2018 Jun 11.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Lung cancer is a devastating disease that remains a top cause of cancer mortality. Despite improvements with targeted and immunotherapies, the majority of patients with lung cancer lack effective therapies, underscoring the need for additional treatment approaches. Genomic studies have identified frequent alterations in components of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A. To understand the mechanisms of tumorigenesis driven by mutations in this complex, we developed a genetically engineered mouse model of lung adenocarcinoma by ablating Smarca4 in the lung epithelium. We demonstrate that Smarca4 acts as a bona fide tumor suppressor and cooperates with p53 loss and Kras activation. Gene expression analyses revealed the signature of enhanced oxidative phosphorylation (OXPHOS) in SMARCA4 mutant tumors. We further show that SMARCA4 mutant cells have enhanced oxygen consumption and increased respiratory capacity. Importantly, SMARCA4 mutant lung cancer cell lines and xenograft tumors have marked sensitivity to inhibition of OXPHOS by a novel small molecule, IACS-010759, that is under clinical development. Mechanistically, we show that SMARCA4-deficient cells have a blunted transcriptional response to energy stress creating a therapeutically exploitable synthetic lethal interaction. These findings provide the mechanistic basis for further development of OXPHOS inhibitors as therapeutics against SWI/SNF mutant tumors.
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http://dx.doi.org/10.1038/s41591-018-0019-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650267PMC
July 2018

Mechanistic insights into the role of truncating PREX2 mutations in melanoma.

Mol Cell Oncol 2016 May 16;3(3):e1160174. Epub 2016 Mar 16.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center , Houston, Texas, USA.

PREX2 is a PTEN binding protein that is significantly mutated in melanoma and pancreatic ductal adenocarcinoma. We recently reported the molecular mechanism of tumorigenesis associated with PREX2 mutations: truncating PREX2 mutations activate its RAC1 guanine nucleotide exchanger activity leading to increased PI3K/AKT signaling and enhanced cell proliferation.
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http://dx.doi.org/10.1080/23723556.2016.1160174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909440PMC
May 2016

Interplay between PREX2 mutations and the PI3K pathway and its effect on epigenetic regulation of gene expression in NRAS-mutant melanoma.

Small GTPases 2016 07 25;7(3):178-85. Epub 2016 Apr 25.

a Department of Genomic Medicine , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.

PREX2 is a PTEN interacting protein that is significantly mutated in melanoma and pancreatic ductal adenocarcinoma. Recently, we reported the mechanistic basis of melanomagenesis by PREX2 mutations. Truncating PREX2 mutations activate its guanine nucleotide exchange factor activity for its substrate RAC1. This leads to increased PI3K/AKT signaling associated with reduced DNA methylation and increased cell proliferation in NRAS-mutant melanoma. Here, we provide additional data that indicates a reciprocal regulation of PREX2 by PTEN whereby loss of PTEN results in a dramatic increase in expression of PREX2 at the protein level. Pharmacologic studies revealed destabilization of PREX2 by inhibition of PI3K/AKT signaling. Additionally, we provide data to show a selective decrease in a particular histone mark, H4 Lys20 trimethylation, in cells expressing PREX2 (E824*) truncating mutation globally and at the imprint control region of CDKN1C (also known as p57) and IGF2. The decrease in H4K20 trimethylation coupled with DNA hypomethylation at this particular locus is associated with genomic imprinting and regulation of expression of p57 and IGF2. Taken together, these results demonstrate the complex signaling mechanisms that involve PREX2, PI3K/AKT/PTEN and downstream epigenetic machinery to deregulate expression of key cell cycle regulators.
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http://dx.doi.org/10.1080/21541248.2016.1178366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003543PMC
July 2016

Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma.

Proc Natl Acad Sci U S A 2016 Mar 16;113(9):E1296-305. Epub 2016 Feb 16.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, TX 77030;

PREX2 (phosphatidylinositol-3,4,5-triphosphate-dependent Rac-exchange factor 2) is a PTEN (phosphatase and tensin homolog deleted on chromosome 10) binding protein that is significantly mutated in cutaneous melanoma and pancreatic ductal adenocarcinoma. Here, genetic and biochemical analyses were conducted to elucidate the nature and mechanistic basis of PREX2 mutation in melanoma development. By generating an inducible transgenic mouse model we showed an oncogenic role for a truncating PREX2 mutation (PREX2(E824)*) in vivo in the context of mutant NRAS. Using integrative cross-species gene expression analysis, we identified deregulated cell cycle and cytoskeleton organization as significantly perturbed biological pathways in PREX2 mutant tumors. Mechanistically, truncation of PREX2 activated its Rac1 guanine nucleotide exchange factor activity, abolished binding to PTEN and activated the PI3K (phosphatidyl inositol 3 kinase)/Akt signaling pathway. We further showed that PREX2 truncating mutations or PTEN deletion induces down-regulation of the tumor suppressor and cell cycle regulator CDKN1C (also known as p57(KIP2)). This down-regulation occurs, at least partially, through DNA hypomethylation of a differentially methylated region in chromosome 11 that is a known regulatory region for expression of the CDKN1C gene. Together, these findings identify PREX2 as a mediator of NRAS-mutant melanoma development that acts through the PI3K/PTEN/Akt pathway to regulate gene expression of a cell cycle regulator.
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http://dx.doi.org/10.1073/pnas.1513801113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780599PMC
March 2016

Melanoma genome sequencing reveals frequent PREX2 mutations.

Nature 2012 May 9;485(7399):502-6. Epub 2012 May 9.

The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)--a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.
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http://dx.doi.org/10.1038/nature11071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367798PMC
May 2012

SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis.

Nature 2011 Mar;471(7340):637-41

Frankfurt Institute for Molecular Life Sciences and Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt, Main, Germany.

SHARPIN is a ubiquitin-binding and ubiquitin-like-domain-containing protein which, when mutated in mice, results in immune system disorders and multi-organ inflammation. Here we report that SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHARPIN causes dysregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in SHARPIN-deficient mice. Upon binding to the LUBAC subunit HOIP (also known as RNF31), SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of SHARPIN and HOIP promotes linear ubiquitination of NEMO (also known as IKBKG), an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, whereas SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L (also known as RBCK1), another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon tumour-necrosis factor α (TNF-α) stimulation via FADD- and caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo.
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http://dx.doi.org/10.1038/nature09814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085511PMC
March 2011

Post-translational modifications in signal integration.

Nat Struct Mol Biol 2010 Jun 23;17(6):666-72. Epub 2010 May 23.

Frankfurt Institute for Molecular Life Sciences and Institute of Biochemistry II, Goethe University, Frankfurt, Germany.

Post-translational modifications of proteins and the domains that recognize these modifications have central roles in creating a highly dynamic relay system that reads and responds to alterations in the cellular microenvironment. Here we review the common principles of post-translational modifications and their importance in signal integration underlying epidermal growth factor receptor signaling and endocytosis, DNA-damage responses and immunity.
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http://dx.doi.org/10.1038/nsmb.1842DOI Listing
June 2010

Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.

Sci Signal 2009 12 22;2(102):ra84. Epub 2009 Dec 22.

Institute of Biochemistry II and Cluster of Excellence Macromolecular Complexes, Goethe University School of Medicine, Frankfurt (Main), Germany.

Binding of epidermal growth factor (EGF) to its receptor leads to receptor dimerization, assembly of protein complexes, and activation of signaling networks that control key cellular responses. Despite their fundamental role in cell biology, little is known about protein complexes associated with the EGF receptor (EGFR) before growth factor stimulation. We used a modified membrane yeast two-hybrid system together with bioinformatics to identify 87 candidate proteins interacting with the ligand-unoccupied EGFR. Among them was histone deacetylase 6 (HDAC6), a cytoplasmic lysine deacetylase, which we found negatively regulated EGFR endocytosis and degradation by controlling the acetylation status of alpha-tubulin and, subsequently, receptor trafficking along microtubules. A negative feedback loop consisting of EGFR-mediated phosphorylation of HDAC6 Tyr(570) resulted in reduced deacetylase activity and increased acetylation of alpha-tubulin. This study illustrates the complexity of the EGFR-associated interactome and identifies protein acetylation as a previously unknown regulator of receptor endocytosis and degradation.
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http://dx.doi.org/10.1126/scisignal.2000576DOI Listing
December 2009

Caspase-8 is involved in neovascularization-promoting progenitor cell functions.

Arterioscler Thromb Vasc Biol 2009 Apr 2;29(4):571-8. Epub 2009 Jan 2.

Department of Internal Medicine III, University of Frankfurt, Frankfurt, Germany.

Objective: Endothelial progenitor cells (EPCs) comprise a heterogeneous population of cells, which improve therapeutic neovascularization after ischemia. The neovascularization-promoting potential of progenitor cells depends on survival and retention of the infused cells to the tissue. Caspases mediate apoptosis but are also involved in other critical biological processes. Therefore, we aimed to address the role of caspases in proangiogenic cells.

Methods And Results: The caspase-8 inhibitor zIETD abrogated the ex vivo formation of EPCs, inhibited EPC adhesion and migration, and reduced their capacity to improve neovascularization in vivo. Consistently, cells isolated from caspase-8-deficient mice exhibited a reduced capacity for enhancing neovascularization when transplanted into mice after hindlimb ischemia. Because inhibition of Caspase-8 reduced the adhesion and homing functions of EPCs, we further determined the surface expression of integrins and receptors involved in cell recruitment to ischemic tissues. Pharmacological inhibition of caspase-8 and genetic depletion of caspase-8 reduced the expression of the fibronectin receptor subunits alpha5 and beta1 and the SDF-1 receptor CXCR4. Moreover, we identified the E3 ubiquitin ligase Cbl-b, which negatively regulates integrin and receptor-mediated signaling, as a potential Caspase-8 substrate.

Conclusions: In summary, our data demonstrate a novel apoptosis-unrelated role of caspase-8 in proangiogenic cells.
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http://dx.doi.org/10.1161/ATVBAHA.108.182006DOI Listing
April 2009

Reply to "The binding stoichiometry of CIN85 SH3 domain A and Cbl-b".

Nat Struct Mol Biol 2008 Sep;15(9):891-2

[1] Division of Molecular Structure, National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK. [2] Present address: Roche Diagnostics, 68305 Mannheim, Germany.

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http://dx.doi.org/10.1038/nsmb0908-891DOI Listing
September 2008

Atypical polyproline recognition by the CMS N-terminal Src homology 3 domain.

J Biol Chem 2006 Dec 3;281(50):38845-53. Epub 2006 Oct 3.

Signal Transduction Group, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, E-28029 Madrid, Spain.

The CIN85/CMS (human homologs of mouse SH3KBP1/CD2AP) family of endocytic adaptor proteins has the ability to engage multiple effectors and couple cargo trafficking with the cytoskeleton. CIN85 and CMS (Cas ligand with multiple Src homology 3 (SH3) domains) facilitate the formation of large multiprotein complexes required for an efficient internalization of cell surface receptors. It has recently been shown that c-Cbl/Cbl-b could mediate the formation of a ternary complex between one c-Cbl/Cbl-b molecule and two SH3 domains of CIN85, important for the ability of Cbl to promote epidermal growth factor receptor down-regulation. To further investigate whether multimerization is conserved within the family of adaptor proteins, we have solved the crystal structures of the CMS N-terminal SH3 domain-forming complexes with Cbl-b- and CD2-derived peptides. Together with biochemical evidence, the structures support the notion that, despite clear differences in the interaction surface, both Cbl-b and CD2 can mediate multimerization of N-terminal CMS SH3 domains. Detailed analyses on the interacting surfaces also provide the basis for a differential Cbl-b molecular recognition of CMS and CIN85.
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http://dx.doi.org/10.1074/jbc.M606411200DOI Listing
December 2006

Cbl promotes clustering of endocytic adaptor proteins.

Nat Struct Mol Biol 2005 Nov;12(11):972-9

Division of Protein Structure, National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.

The ubiquitin ligases c-Cbl and Cbl-b play a crucial role in receptor downregulation by mediating multiple monoubiquitination of receptors and promoting their sorting for lysosomal degradation. Their function is modulated through interactions with regulatory proteins including CIN85 and PIX, which recognize a proline-arginine motif in Cbl and thus promote or inhibit receptor endocytosis. We report the structures of SH3 domains of CIN85 and beta-PIX in complex with a proline-arginine peptide from Cbl-b. Both structures reveal a heterotrimeric complex containing two SH3 domains held together by a single peptide. Trimerization also occurs in solution and is facilitated by the pseudo-symmetrical peptide sequence. Moreover, ternary complexes of CIN85 and Cbl are formed in vivo and are important for the ability of Cbl to promote epidermal growth factor receptor (EGFR) downregulation. These results provide molecular explanations for a novel mechanism by which Cbl controls receptor downregulation.
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http://dx.doi.org/10.1038/nsmb1000DOI Listing
November 2005