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Article ; Online: The Wearable Cardioverter Defibrillator-Bridge to the Implantable Defibrillator.

Klein, Helmut U / Cygankiewicz, Iwona / Jons, Christian / Buhtz, Frank / Szymkiewicz, Steven

Cardiac electrophysiology clinics

2009 Volume 1, Issue 1, Page(s) 129–146

Abstract: The wearable cardioverter defibrillator (WCD) was introduced into clinical practice about 8 years ago as an alternative approach to protect patients with a temporary high risk of sudden arrhythmic death. The WCD has the characteristics of an implantable ... ...

Abstract	The wearable cardioverter defibrillator (WCD) was introduced into clinical practice about 8 years ago as an alternative approach to protect patients with a temporary high risk of sudden arrhythmic death. The WCD has the characteristics of an implantable defibrillator (ICD) but does not need to be implanted, and it has similarities with an external defibrillator, but does not require a bystander to apply lifesaving shocks when necessary. Based on current clinical experience, the WCD is not an alternative to the ICD, but a device that will contribute to better selection of patients for ICD therapy and may be indicated in case of interrupted protection by an already implanted ICD, temporary inability to implant an ICD, or refusal of an indicated ICD.
Language	English
Publishing date	2009-12
Publishing country	United States
Document type	Journal Article
ISSN	1877-9190
ISSN (online)	1877-9190
DOI	10.1016/j.ccep.2009.08.007
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Article ; Online: Cargo- and compartment-selective endocytic scaffold proteins.

Szymkiewicz, Iwona / Shupliakov, Oleg / Dikic, Ivan

The Biochemical journal

2004 Volume 383, Issue Pt 1, Page(s) 1–11

Abstract: The endocytosis of membrane receptors is a complex and tightly controlled process that is essential for maintaining cellular homoeostasis. The removal of receptors from the cell surface can be constitutive or ligand-induced, and occurs in a clathrin- ... ...

Abstract	The endocytosis of membrane receptors is a complex and tightly controlled process that is essential for maintaining cellular homoeostasis. The removal of receptors from the cell surface can be constitutive or ligand-induced, and occurs in a clathrin-dependent or -independent manner. The recruitment of receptors into specialized membrane domains, the formation of vesicles and the trafficking of receptors together with their ligands within endocytic compartments are regulated by reversible protein modifications, and multiple protein-protein and protein-lipid interactions. Recent reports describe a variety of multidomain molecules that facilitate receptor endocytosis and function as platforms for the assembly of protein complexes. These scaffold proteins typically act in a cargo-specific manner, recognizing one or more receptor types, or function at the level of endocytic cellular microcompartments by controlling the movement of cargo molecules and linking endocytic machineries to signalling pathways. In the present review we summarize present knowledge on endocytic scaffold molecules and discuss their functions.
MeSH term(s)	Adaptor Proteins, Signal Transducing/physiology ; Adaptor Proteins, Vesicular Transport/physiology ; Carrier Proteins/physiology ; Cell Compartmentation/physiology ; Cytoplasmic Vesicles/chemistry ; Cytoplasmic Vesicles/physiology ; Cytoskeletal Proteins/physiology ; Endocytosis/physiology ; Membrane Proteins/physiology ; Receptors, Cell Surface/metabolism ; Vesicular Transport Proteins/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport ; Carrier Proteins ; Cytoskeletal Proteins ; Membrane Proteins ; Receptors, Cell Surface ; Vesicular Transport Proteins
Language	English
Publishing date	2004-06-25
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BJ20040913
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Article: SH3P2 in complex with Cbl and Src.

Szymkiewicz, Iwona / Destaing, Olivier / Jurdic, Pierre / Dikic, Ivan

FEBS letters

2004 Volume 565, Issue 1-3, Page(s) 33–38

Abstract: In this report, we describe SH3P2, an SH3-domain containing protein, as a novel Cbl-interacting molecule that is a substrate of tyrosine kinase Src. We identified a specific polyproline motif of Cbl responsible for binding of SH3P2 and Src, and observed ... ...

Abstract	In this report, we describe SH3P2, an SH3-domain containing protein, as a novel Cbl-interacting molecule that is a substrate of tyrosine kinase Src. We identified a specific polyproline motif of Cbl responsible for binding of SH3P2 and Src, and observed mutual sequestration of Src and SH3P2 from monomer Cbl molecules. In adherent cells, SH3P2 associated with Cbl and fibrilar actin and was localized at focal contacts in fibroblasts as well as at the apical part of podosome rings in differentiated osteoclasts. Our data implicate that SH3P2, a novel component of adhesion sites, is involved in Cbl and Src-mediated pathways.
MeSH term(s)	Actins/chemistry ; Actins/metabolism ; Amino Acid Motifs ; Animals ; Cell Adhesion ; Cell Line ; DNA, Complementary/metabolism ; Fibroblasts/metabolism ; Fluorescent Antibody Technique, Indirect ; Focal Adhesions/metabolism ; HeLa Cells ; Humans ; Male ; Mice ; Models, Biological ; NIH 3T3 Cells ; Oncogene Protein v-cbl ; Osteoclasts/metabolism ; Peptides/chemistry ; Peptides/metabolism ; Peptides/physiology ; Phosphorylation ; Phosphotyrosine/chemistry ; Plasmids/metabolism ; Precipitin Tests ; Protein Binding ; Retroviridae Proteins, Oncogenic/metabolism ; Spleen/cytology ; Transfection ; Two-Hybrid System Techniques ; Tyrosine/metabolism ; src-Family Kinases/metabolism
Chemical Substances	Actins ; DNA, Complementary ; Oncogene Protein v-cbl ; Peptides ; Retroviridae Proteins, Oncogenic ; osteoclast stimulating factor ; Phosphotyrosine (21820-51-9) ; polyproline (25191-13-3) ; Tyrosine (42HK56048U) ; src-Family Kinases (EC 2.7.10.2)
Language	English
Publishing date	2004-05-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1016/j.febslet.2004.03.100
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Article: Cbl-ArgBP2 complex mediates ubiquitination and degradation of c-Abl.

Soubeyran, Philippe / Barac, Ana / Szymkiewicz, Iwona / Dikic, Ivan

The Biochemical journal

2003 Volume 370, Issue Pt 1, Page(s) 29–34

Abstract: The mechanisms leading to the ubiquitination and degradation of the activated c-Abl kinase have not yet been identified. We found that the multi-adaptor protein ArgBP2 links c-Abl to the ubiquitin ligase Cbl. Phosphorylation of Cbl and ArgBP2 by c-Abl ... ...

Abstract	The mechanisms leading to the ubiquitination and degradation of the activated c-Abl kinase have not yet been identified. We found that the multi-adaptor protein ArgBP2 links c-Abl to the ubiquitin ligase Cbl. Phosphorylation of Cbl and ArgBP2 by c-Abl resulted in the stabilization of their interactions, thus facilitating Cbl-induced ubiquitination and subsequent degradation of c-Abl and ArgBP2.
MeSH term(s)	Animals ; CHO Cells ; Cricetinae ; Homeodomain Proteins/metabolism ; Humans ; Hydrolysis ; Oncogene Protein v-cbl ; Phosphorylation ; Protein Binding ; Proto-Oncogene Proteins c-abl/metabolism ; Retroviridae Proteins, Oncogenic/metabolism ; Two-Hybrid System Techniques ; Ubiquitin/metabolism
Chemical Substances	Homeodomain Proteins ; Oncogene Protein v-cbl ; Retroviridae Proteins, Oncogenic ; SORBS2 protein, human ; Ubiquitin ; Proto-Oncogene Proteins c-abl (EC 2.7.10.2)
Language	English
Publishing date	2003-02-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2969-5
ISSN	1470-8728 ; 0264-6021 ; 0006-2936 ; 0306-3275
ISSN (online)	1470-8728
ISSN	0264-6021 ; 0006-2936 ; 0306-3275
DOI	10.1042/BJ20021539
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Article: Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors.

Haglund, Kaisa / Shimokawa, Noriaki / Szymkiewicz, Iwona / Dikic, Ivan

Proceedings of the National Academy of Sciences of the United States of America

2002 Volume 99, Issue 19, Page(s) 12191–12196

Abstract: Addition of ubiquitin or ubiquitin chains to target proteins leads to their mono- or polyubiquitination, respectively. Whereas polyubiquitination targets proteins for degradation, monoubiquitination is thought to regulate receptor internalization and ... ...

Abstract	Addition of ubiquitin or ubiquitin chains to target proteins leads to their mono- or polyubiquitination, respectively. Whereas polyubiquitination targets proteins for degradation, monoubiquitination is thought to regulate receptor internalization and endosomal sorting. Cbl proteins are major ubiquitin ligases that promote ligand-dependent polyubiquitination and degradation of receptor tyrosine kinases. They also recruit CIN85-endophilin in the complex with activated receptors, thus controlling receptor endocytosis. Here we show that the adaptor protein CIN85 and its homologue CMS are monoubiquitinated by Cbl/Cbl-b after epidermal growth factor (EGF) stimulation. Monoubiquitination of CIN85 required direct interactions between CIN85 and Cbl, the intact RING finger domain of Cbl and a ubiquitin acceptor site present in the carboxyl terminus of CIN85. Cbl-b and monoubiquitinated CIN85 are found in the complex with polyubiquitinated EGF receptors during prolonged EGF stimulation and are degraded together in the lysosome. Dominant interfering forms of CIN85, which have been shown previously to delay EGF receptor degradation, were also impaired in their monoubiquitination. Thus, our data demonstrate that Cbl/Cbl-b can mediate polyubiquitination of cargo as well as monoubiquitination of CIN85 to control endosomal sorting and degradation of receptor tyrosine kinases.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Animals ; Carrier Proteins/chemistry ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line ; Cytoskeletal Proteins ; Epidermal Growth Factor/pharmacology ; Humans ; In Vitro Techniques ; Ligands ; Models, Biological ; Mutagenesis, Site-Directed ; Oncogene Protein v-cbl ; Receptor, Epidermal Growth Factor/genetics ; Receptor, Epidermal Growth Factor/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Retroviridae Proteins, Oncogenic/genetics ; Retroviridae Proteins, Oncogenic/metabolism ; Ubiquitin/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; CD2-associated protein ; Carrier Proteins ; Cytoskeletal Proteins ; Ligands ; Oncogene Protein v-cbl ; Recombinant Proteins ; Retroviridae Proteins, Oncogenic ; SH3KBP1 protein, human ; Ubiquitin ; Epidermal Growth Factor (62229-50-9) ; Receptor, Epidermal Growth Factor (EC 2.7.10.1)
Language	English
Publishing date	2002-09-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.192462299
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Article: Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation.

Haglund, Kaisa / Sigismund, Sara / Polo, Simona / Szymkiewicz, Iwona / Di Fiore, Pier Paolo / Dikic, Ivan

Nature cell biology

2003 Volume 5, Issue 5, Page(s) 461–466

Abstract: Many cellular proteins are post-translationally modified by the addition of a single ubiquitin or a polyubiquitin chain. Among these are receptor tyrosine kinases (RTKs), which undergo ligand-dependent ubiquitination. The ubiquitination of RTKs has ... ...

Abstract	Many cellular proteins are post-translationally modified by the addition of a single ubiquitin or a polyubiquitin chain. Among these are receptor tyrosine kinases (RTKs), which undergo ligand-dependent ubiquitination. The ubiquitination of RTKs has become recognized as an important signal for their endocytosis and degradation in the lysosome; however, it is not clear whether ubiquitination itself is sufficient for this process or simply participates in its regulation. The issue is further complicated by the fact that RTKs are thought to be polyubiquitinated - a modification that is linked to protein degradation by the proteasome. By contrast, monoubiquitination has been associated with diverse proteasome-independent cellular functions including intracellular protein movement. Here we show that the epidermal growth factor and platelet-derived growth factor receptors are not polyubiquitinated but rather are monoubiquitinated at multiple sites after their ligand-induced activation. By using different biochemical and molecular genetics approaches, we show that a single ubiquitin is sufficient for both receptor internalization and degradation. Thus, monoubiquitination is the principal signal responsible for the movement of RTKs from the plasma membrane to the lysosome.
MeSH term(s)	Animals ; CHO Cells ; Cell Membrane/metabolism ; Cricetinae ; Cysteine Endopeptidases/metabolism ; Endocytosis/physiology ; ErbB Receptors/metabolism ; Eukaryotic Cells/metabolism ; HeLa Cells ; Humans ; Lysosomes/metabolism ; Mice ; Multienzyme Complexes/metabolism ; Proteasome Endopeptidase Complex ; Protein Transport/physiology ; Receptor Protein-Tyrosine Kinases/metabolism ; Receptors, Platelet-Derived Growth Factor/metabolism ; Ubiquitin/metabolism
Chemical Substances	Multienzyme Complexes ; Ubiquitin ; ErbB Receptors (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; Receptors, Platelet-Derived Growth Factor (EC 2.7.10.1) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2003-04-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/ncb983
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Article ; Online: Bridging a temporary high risk of sudden arrhythmic death. Experience with the wearable cardioverter defibrillator (WCD).

Klein, Helmut U / Meltendorf, Ulf / Reek, Sven / Smid, Jan / Kuss, Sebastian / Cygankiewicz, Iwona / Jons, Christian / Szymkiewicz, Steven / Buhtz, Frank / Wollbrueck, Anke / Zareba, Wojciech / Moss, Arthur J

Pacing and clinical electrophysiology : PACE

2010 Volume 33, Issue 3, Page(s) 353–367

Abstract: The implantable cardioverter defibrillator (ICD) is able to reduce sudden arrhythmic death in patients who are considered to be at high risk. However, the arrhythmic risk may be increased only temporarily as long as the proarrhythmic conditions persist, ... ...

Abstract	The implantable cardioverter defibrillator (ICD) is able to reduce sudden arrhythmic death in patients who are considered to be at high risk. However, the arrhythmic risk may be increased only temporarily as long as the proarrhythmic conditions persist, left ventricular ejection fraction remains low, or heart failure prevails. The wearable cardioverter defibrillator (WCD) represents an alternative approach to prevent sudden arrhythmic death until either ICD implantation is clearly indicated or the arrhythmic risk is considered significantly lower or even absent. The WCD is also indicated for interrupted protection by an already implanted ICD, temporary inability to implant an ICD, and lastly refusal of an indicated ICD by the patient. The WCD is not an alternative to the ICD, but a device that may contribute to better selection of patients for ICD therapy. The WCD has the characteristics of an ICD, but does not need to be implanted, and it has similarities with an external defibrillator, but does not require a bystander to apply lifesaving shocks when necessary. The WCD was introduced into clinical practice about 8 years ago, and indications for its use are currently expanding. This article describes the technological aspects of the WCD, discusses current indications for its use, and reviews the clinical studies with the WCD. Additionally, data are reported on the clinical experience with the WCD based on 354 patients from Germany hospitalized between 2000 and 2008 who wore the WCD for a mean of 3 months.
MeSH term(s)	Death, Sudden, Cardiac/prevention & control ; Defibrillators, Implantable ; Electric Countershock/instrumentation ; Equipment Design ; Equipment Failure ; Humans ; Patient Satisfaction ; Risk Assessment ; Tachycardia, Ventricular/therapy
Language	English
Publishing date	2010-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	424437-0
ISSN	1540-8159 ; 0147-8389
ISSN (online)	1540-8159
ISSN	0147-8389
DOI	10.1111/j.1540-8159.2009.02590.x
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Article: Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors.

Soubeyran, Philippe / Kowanetz, Katarzyna / Szymkiewicz, Iwona / Langdon, Wallace Y / Dikic, Ivan

Nature

2002 Volume 416, Issue 6877, Page(s) 183–187

Abstract: Cbl is a multi-adaptor protein involved in ligand-induced downregulation of receptor tyrosine kinases. It is thought that Cbl-mediated ubiquitination of active receptors is essential for receptor degradation and cessation of receptor-induced signal ... ...

Abstract	Cbl is a multi-adaptor protein involved in ligand-induced downregulation of receptor tyrosine kinases. It is thought that Cbl-mediated ubiquitination of active receptors is essential for receptor degradation and cessation of receptor-induced signal transduction. Here we demonstrate that Cbl additionally regulates epidermal growth factor (EGF) receptor endocytosis. Cbl rapidly recruits CIN85 (Cbl-interacting protein of 85K; ref. 6) and endophilins (regulatory components of clathrin-coated vesicles) to form a complex with activated EGF receptors, thus controlling receptor internalization. CIN85 was constitutively associated with endophilins, whereas CIN85 binding to the distal carboxy terminus of Cbl was increased on EGF stimulation. Inhibition of these interactions was sufficient to block EGF receptor internalization, delay receptor degradation and enhance EGF-induced gene transcription, without perturbing Cbl-directed receptor ubiquitination. Thus, the evolutionary divergent C terminus of Cbl uses a mechanism that is functionally separable from the ubiquitin ligase activity of Cbl to mediate ligand-dependent downregulation of receptor tyrosine kinases.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Animals ; CHO Cells ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line ; Cricetinae ; Down-Regulation/drug effects ; Endocytosis/drug effects ; Epidermal Growth Factor/pharmacology ; Genes, Reporter/genetics ; Humans ; Ligands ; Macromolecular Substances ; Precipitin Tests ; Protein Binding/drug effects ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-cbl ; Receptor, Epidermal Growth Factor/metabolism ; Ubiquitin-Protein Ligases
Chemical Substances	Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Ligands ; Macromolecular Substances ; Proto-Oncogene Proteins ; SH3GL2 protein, human ; SH3KBP1 protein, human ; Epidermal Growth Factor (62229-50-9) ; Proto-Oncogene Proteins c-cbl (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Receptor, Epidermal Growth Factor (EC 2.7.10.1) ; CBL protein, human (EC 6.3.2.-)
Language	English
Publishing date	2002-03-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/416183a
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Article: CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine kinases.

Szymkiewicz, Iwona / Kowanetz, Katarzyna / Soubeyran, Philippe / Dinarina, Ana / Lipkowitz, Stanley / Dikic, Ivan

The Journal of biological chemistry

2002 Volume 277, Issue 42, Page(s) 39666–39672

Abstract: The Cbl family of ubiquitin ligases in mammals contains three members, Cbl, Cbl-b, and Cbl-3, that are involved in down-regulation of receptor tyrosine kinases (RTKs) by mediating receptor ubiquitination and degradation. More recently, a novel pathway ... ...

Abstract	The Cbl family of ubiquitin ligases in mammals contains three members, Cbl, Cbl-b, and Cbl-3, that are involved in down-regulation of receptor tyrosine kinases (RTKs) by mediating receptor ubiquitination and degradation. More recently, a novel pathway has been identified whereby Cbl promotes internalization of EGF receptor via a CIN85/endophilin pathway that is functionally separable from the ubiquitin ligase activity of Cbl (1). Here we show that Cbl-b, but not Cbl-3, utilize the same mechanism to down-regulate multiple RTKs. CIN85 was shown to bind to the minimal binding domain identified in the carboxyl terminus of Cbl-b. Ligand-induced phosphorylation of Cbl-b further increased their interactions and led to a rapid and sustained recruitment of CIN85 in the complex with EGF or PDGF receptors. Inhibition of binding between CIN85 and Cbl-b was sufficient to impair Cbl-b-mediated internalization of EGF receptors, while being dispensable for Cbl-b-directed polyubiquitination of EGF receptors. Moreover, CIN85 and Cbl/Cbl-b were constitutively associated with activated PDGF, EGF, or c-Kit receptors in several tumor cell lines. Our data reveal a common pathway utilized by Cbl and Cbl-b that may have an important and redundant function in negative regulation of ligand-activated as well as oncogenically activated RTKs in vivo.
MeSH term(s)	3T3 Cells ; Adaptor Proteins, Signal Transducing ; Animals ; CHO Cells ; Carrier Proteins/metabolism ; Cell Line ; Cell Line, Transformed ; Cloning, Molecular ; Cricetinae ; Down-Regulation ; Endocytosis ; Epidermal Growth Factor/metabolism ; HeLa Cells ; Humans ; Ligands ; Mice ; Microscopy, Fluorescence ; Models, Biological ; Phosphoproteins/metabolism ; Phosphorylation ; Platelet-Derived Growth Factor/metabolism ; Precipitin Tests ; Protein Binding ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-cbl ; Proto-Oncogene Proteins c-kit/metabolism ; Receptor Protein-Tyrosine Kinases/metabolism ; Time Factors ; Transfection ; Two-Hybrid System Techniques ; Ubiquitin-Protein Ligases
Chemical Substances	Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Cblb protein, mouse ; Ligands ; Phosphoproteins ; Platelet-Derived Growth Factor ; SH3KBP1 protein, human ; Epidermal Growth Factor (62229-50-9) ; CBLB protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-cbl (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Proto-Oncogene Proteins c-kit (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2002-08-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M205535200
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Article: Identification of a novel proline-arginine motif involved in CIN85-dependent clustering of Cbl and down-regulation of epidermal growth factor receptors.

Kowanetz, Katarzyna / Szymkiewicz, Iwona / Haglund, Kaisa / Kowanetz, Marcin / Husnjak, Koraljka / Taylor, Jonathan D / Soubeyran, Philippe / Engstrom, Ulla / Ladbury, John E / Dikic, Ivan

The Journal of biological chemistry

2003 Volume 278, Issue 41, Page(s) 39735–39746

Abstract: CIN85 is a multidomain adaptor protein implicated in Cbl-mediated down-regulation of receptor tyrosine kinases. CIN85 binding to Cbl is increased after growth factor stimulation and is critical for targeting receptor tyrosine kinases to clathrin-mediated ...

Abstract	CIN85 is a multidomain adaptor protein implicated in Cbl-mediated down-regulation of receptor tyrosine kinases. CIN85 binding to Cbl is increased after growth factor stimulation and is critical for targeting receptor tyrosine kinases to clathrin-mediated endocytosis. Here we report the identification of a novel polyproline-arginine motif (PXXXPR), specifically recognized by the SH3 domains of CIN85 and its homologue CMS/CD2AP. This motif was indispensable for CIN85 binding to Cbl/Cbl-b, to other CIN85 SH3 domains' effectors, and for mediating an intramolecular interaction between the SH3-A domain and the proline-rich region of CIN85. Individual SH3 domains of CIN85 bound to PXXXPR peptides of Cbl/Cbl-b with micromolar affinities, whereas an extended structure of two or three SH3 domains bound with higher stoichiometry and increased affinity to the same peptides. This enabled full size CIN85 to simultaneously interact with multiple Cbl molecules, promoting their clustering in mammalian cells. The ability of CIN85 to cluster Cbl was important for ligand-induced stabilization of CIN85.Cbl.epidermal growth factor receptor complexes, as well as for epidermal growth factor receptor degradation in the lysosome. Thus, specific interactions of CIN85 SH3 domains with the PXXXPR motif in Cbl play multiple roles in down-regulation of receptor tyrosine kinases.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Arginine/chemistry ; Binding Sites ; CHO Cells ; Carrier Proteins/chemistry ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line ; Consensus Sequence ; Cricetinae ; Down-Regulation ; Endocytosis ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Humans ; In Vitro Techniques ; Molecular Sequence Data ; Oncogene Protein v-cbl ; Phosphoproteins/chemistry ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Proline/chemistry ; Proto-Oncogene Proteins c-cbl ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Retroviridae Proteins, Oncogenic/chemistry ; Retroviridae Proteins, Oncogenic/genetics ; Retroviridae Proteins, Oncogenic/metabolism ; Sequence Homology, Amino Acid ; Ubiquitin-Protein Ligases ; src Homology Domains
Chemical Substances	Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Oncogene Protein v-cbl ; Phosphoproteins ; Recombinant Proteins ; Retroviridae Proteins, Oncogenic ; SH3KBP1 protein, human ; Arginine (94ZLA3W45F) ; Proline (9DLQ4CIU6V) ; CBLB protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-cbl (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2003-07-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M304541200
Database	MEDical Literature Analysis and Retrieval System OnLINE

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