Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule βPix

Schmidt, Mirko H. H.; Husnjak, Koraljka; Szymkiewicz, Iwona; Haglund, Kaisa; Đikić, Ivan

doi:10.1038/sj.onc.1209329

Cited by 39 publications

(40 citation statements)

References 26 publications

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“…Further studies on Src-transformed cells revealed that Cool-1 phosphorylation status modulates their migration and invasive activity [16]. In addition, previous studies (using overexpression analyses) reported that a complex of Cdc42 and Cool-1 is required to inhibit c-Cbl [11,30]. In contrast, our studies demonstrate the importance of Cool-1 and its inhibition of c-Cbl in at least a subset of naturally occurring GBMs, one of the most deadly human cancers.…”

Section: Discussioncontrasting

confidence: 52%

“…In comparison, disruption of c-Cbl by inhibitory proteins has received much less attention. Previous studies on human tumors showed that Cdc42 knockdown in breast cancer cells reduces proliferation and migration and enables reductions in EGFR levels (apparently in a c-Cbl dependent manner [11,12,30]), but these studies did not examine tumor initiation or consequences of Cdc42 knockdown on sensitivity to therapeutic agents. In addition, recent studies on GBM cells isolated and grown in conditions that do not select for TICs raise the possibility that c-Cbl also may be inhibited by transglutaminase-2 [31].…”

Section: Discussionmentioning

confidence: 99%

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Cool‐1‐Mediated Inhibition of c‐Cbl Modulates Multiple Critical Properties of Glioblastomas, Including the Ability to Generate Tumors In Vivo

et al. 2014

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We discovered that glioblastoma (GBM) cells use Cool-1/b-pix to inhibit normal activation of the c-Cbl ubiquitin ligase via the redox/Fyn/c-Cbl pathway and that c-Cbl inhibition is critical for GBM cell function. Restoring normal c-Cbl activity by Cool-1 knockdown in vitro reduced GBM cell division, almost eliminated generation of adhesion-independent spheroids, reduced the representation of cells expressing antigens thought to identify tumor initiating cells (TICs), reduced levels of several proteins of critical importance in TIC function (such as Notch-1 and Sox2), and increased sensitivity to BCNU (carmustine) and temozolomide (TMZ). In vivo, Cool-1 knockdown greatly suppressed the ability of GBM cells to generate tumors, an outcome that was c-Cbl dependent. In contrast, Cool-1 knockdown did not reduce division or increase BCNU or TMZ sensitivity in primary glial progenitor cells and Cool-1/c-Cbl complexes were not found in normal brain tissue. Our studies provide the first evidence that Cool-1 may be critical in the biology of human tumors, that suppression of c-Cbl by Cool-1 may be critical for generation of at least a subset of GBMs and offer a novel target that appears to be selectively necessary for TIC function and modulates chemoresistance in GBM cells. Targeting such proteins that inhibit c-Cbl offers potentially attractive opportunities for therapeutic development. STEM CELLS

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Cool‐1‐Mediated Inhibition of c‐Cbl Modulates Multiple Critical Properties of Glioblastomas, Including the Ability to Generate Tumors In Vivo

et al. 2014

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“…AIP4 Binds to the CIN85 Scaffolding Protein-The ␤PIX-SH3 domain is phylogenetically similar to the three SH3 domains of CIN85, an adaptor protein involved in Cbl-mediated downregulation of RTKs (9,26). Like ␤PIX, the SH3 domains of CIN85 recognize and bind the non-canonical PXXXPR motifs in Cbl and PAK proteins (26,28,39).…”

Section: Resultsmentioning

confidence: 99%

“…Like ␤PIX, the SH3 domains of CIN85 recognize and bind the non-canonical PXXXPR motifs in Cbl and PAK proteins (26,28,39). When both FLAG-tagged CIN85 and Myc-tagged AIP4 were co-expressed in HEK293T cells we found that CIN85 pulled down AIP4, albeit to a lesser extent than ␤PIX (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Although most SH3 domain ligands contain a PXXP motif, ␤PIX-SH3 binds ligands with a non-canonical PXXXPR sequence and serves as a scaffolding point for a number of protein-protein interactions as demonstrated by the direct coupling of ␤PIX to p21-activated kinase (PAK) family members (20). The ␤PIX-SH3 domain also binds to the PXXXPR motif of Cbl family members to facilitate the clustering of proteins involved in the down-regulation of EGF receptor signaling (26,28). Interestingly, the ␤PIX-SH3 domain also binds proteins, including Rac1 and SAP (signaling lymphocyte activation molecule-associated protein) (29, 30) that possess neither the * This work was supported in part by the Allene Reuss Memorial Trust and the Howard Hughes Medical Institute.…”

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confidence: 99%

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A Novel Interaction between Atrophin-interacting Protein 4 and β-p21-activated Kinase-interactive Exchange Factor Is Mediated by an SH3 Domain

Janz

Sakmar

Min

2007

Journal of Biological Chemistry

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Cross-talk between G protein-coupled receptors and receptor tyrosine kinase signaling pathways is crucial to the efficient relay and integration of cellular information. Here we identify and define the novel binding interaction of the E3 ubiquitin ligase atrophin-interacting protein 4 (AIP4) with the GTP exchange factor ␤-p21-activated kinase-interactive exchange factor (␤PIX). We demonstrate that this interaction is mediated in part by the ␤PIX-SH3 domain binding to a proline-rich stretch of AIP4. Analysis of the interaction by isothermal calorimetry is consistent with a heterotrimeric complex with one AIP4-derived peptide binding to two ␤PIX-SH3 domains. We determined the crystal structure of the ␤PIX-SH3⅐AIP4 complex to 2.0-Å resolution. In contrast to the calorimetry results, the crystal structure shows a monomeric complex in which AIP4 peptide binds the ␤PIX-SH3 domain as a canonical Class I ligand with an additional type II polyproline helix that makes extensive contacts with another face of ␤PIX. Taken together, the novel interaction between AIP4 and ␤PIX represents a new regulatory node for G protein-coupled receptor and receptor tyrosine kinase signal integration. Our structure of the ␤PIX-SH3⅐AIP4 complex provides important insight into the mechanistic basis for ␤PIX scaffolding of signaling components, especially those involved in cross-talk.Two prominent transmembrane receptor families facilitate cellular communication with the extracellular environment: G protein-coupled receptors (GPCRs) 4 and receptor tyrosine kinases (RTKs). A wide array of ligands bind to these receptors to orchestrate signaling networks integral to many cellular functions. Internalization and degradation of receptor molecules from both families regulate signal duration and termination (1, 2). E3 ubiquitin ligases, which catalyze the ubiquitination of receptors, control intracellular sorting, recycling, and degradation (3-5). Representative E3 ligases include atrophininteracting protein 4 (AIP4), which ubiquitinates the GPCR chemokine receptor CXCR4 (6) and Cbl (Casitas B-lymphoma protein), which ubiquitinates the RTK epidermal growth factor (EGF) receptor (7-9). The importance of signal termination control is exemplified by recent work implicating prolonged signaling as a cause of cellular transformation (10, 11). In addition to mediating the ubiquitination and sorting of CXCR4, a number of recent studies detail the regulatory role AIP4 plays in developmental, immunological, and oncogenic signaling pathways (12-18). The AIP4/Itch protein is composed of an N-terminal C2 domain, followed by a proline-rich region, four WW domains, and a C-terminal catalytic HECT domain (3,4,12,13). AIP4 is abundantly expressed in most human tissues and displays tissue specificity similar to that of Cbl (19).␤-PAK-interactive exchange factor (␤PIX also referred to as Cool-1) is composed of modular domains, including an N-terminal SH3 domain followed by DH (Dbl, diffuse B-cell lymphoma homology) domain, PH (pleckstrin homology) domain, and a leucine...

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Inhibition of redox/Fyn/c‐Cbl pathway function by Cdc42 controls tumour initiation capacity and tamoxifen sensitivity in basal‐like breast cancer cells

et al. 2013

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We found that basal-like breast cancer (BLBC) cells use Cdc42 to inhibit function of the redox/Fyn/c-Cbl (RFC) pathway, which normally functions to convert small increases in oxidative status into enhanced degradation of c-Cbl target proteins. Restoration of RFC pathway function by genetic or pharmacological Cdc42 inhibition enabled harnessing of pro-oxidant effects of low µM tamoxifen (TMX) concentrations – concentrations utilized in trials on multiple tumour types – to suppress division and induce death of BLBC cells in vitro and to confer TMX sensitivity in vivo through oestrogen receptor-α-independent mechanisms. Cdc42 knockdown also inhibited generation of mammospheres in vitro and tumours in vivo, demonstrating the additional importance of this pathway in tumour initiating cell (TIC) function. These findings provide a new regulatory pathway that is subverted in cancer cells, a novel means of attacking TIC and non-TIC aspects of BLBCs, a lead molecule (ML141) that confers sensitivity to low µM TMX in vitro and in vivo and also appear to be novel in enhancing sensitivity to a non-canonical mode of action of an established therapeutic agent.

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Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule βPix

Cited by 39 publications

References 26 publications

Cool‐1‐Mediated Inhibition of c‐Cbl Modulates Multiple Critical Properties of Glioblastomas, Including the Ability to Generate Tumors In Vivo

Cool‐1‐Mediated Inhibition of c‐Cbl Modulates Multiple Critical Properties of Glioblastomas, Including the Ability to Generate Tumors In Vivo

A Novel Interaction between Atrophin-interacting Protein 4 and β-p21-activated Kinase-interactive Exchange Factor Is Mediated by an SH3 Domain

Inhibition of redox/Fyn/c‐Cbl pathway function by Cdc42 controls tumour initiation capacity and tamoxifen sensitivity in basal‐like breast cancer cells

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