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SH3P2 is a novel Cbl-interacting protein that participates in regulation of actin dynamics
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Ecole Normale Supérieure de Lyon, UMR 5665 CNRS/ENS/INRA 913, 46 allée d'Italie, 69364 Lyon Cedex 07, France.
Ecole Normale Supérieure de Lyon, UMR 5665 CNRS/ENS/INRA 913, 46 allée d'Italie, 69364 Lyon Cedex 07, France.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Institute of Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
2004 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 565, no 1-3, 33-38 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier B.V. , 2004. Vol. 565, no 1-3, 33-38 p.
Keyword [en]
Actin; Cbl; Osteoclast; Podosome; SH3; Src
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-90467DOI: 10.1016/j.febslet.2004.03.100PubMedID: 15135048OAI: oai:DiVA.org:uu-90467DiVA: diva2:162830
Available from: 2003-04-28 Created: 2003-04-28 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Cbl in Regulation of Growth Factor Receptor Endocytosis and Actin Dynamics
Open this publication in new window or tab >>Cbl in Regulation of Growth Factor Receptor Endocytosis and Actin Dynamics
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins belonging to the Cbl family are multidomain scaffolds that participate in numerous processes, assembling signaling complexes and mediating attachment of ubiquitin to receptor and non-receptor tyrosine kinases.

We characterized a novel role for Cbl and Cbl-b in ligand-dependent internalization of growth factor receptors. Upon stimulation with epidermal growth factor (EGF), Cbl proteins associate with EGF receptor, become phosphorylated, and bind to the three SH3 domains of CIN85, which brings endophilins to the complex with active receptors. Endophilins can induce internalization of the plasma membrane, contributing to formation of clathrin-coated pits. We identified a minimal binding domain for CIN85 in the carboxyl termini of Cbl/Cbl-b and observed constitutive association between CIN85, Cbl/Cbl-b and oncogenically stimulated receptor tyrosine kinases. In addition to functioning as a ubiquitin ligase, Cbl forms a complex with CIN85 and endophilin, which is required for efficient endocytosis and downregulation of membrane receptors.

In EGF stimulated cells, we observed inducible modification of CIN85 and related CMS proteins by attachment of a single ubiquitin molecule. Monoubiquitination of CIN85 was mediated by the RING finger and dependent on the carboxyl terminal part of Cbl/Cbl-b, and demanded an intact carboxyl terminus of CIN85. Prolonged stimulation with EGF induced concomitant degradation of EGF receptors, Cbl, and monoubiquitinated forms of CIN85 in lysosomes.

Cbl regulates cytoskeletal processes in a variety of cell systems. We identified SH3P2, a protein with SH3 domain and ankyrin repeats, as a Cbl partner and described its phosphorylation by Src and its distribution in fibroblasts and osteoclasts. SH3P2 formed inducible complexes with Cbl and actin in spread cells and colocalized with dynamic actin structures.

Our data contribute to better understanding of the role of Cbl in downregulation of receptor tyrosine kinases as well as in controlling actin rearrangement.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 58 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1243
Keyword
Cell and molecular biology, RTK, Cbl, endocytosis, ubiquitination, actin, Cell- och molekylärbiologi
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Cellbiology
Identifiers
urn:nbn:se:uu:diva-3443 (URN)91-554-5583-2 (ISBN)
Public defence
2003-05-22, B42, Biomedical Center (BMC), Uppsala, 13:15
Opponent
Supervisors
Available from: 2003-04-28 Created: 2003-04-28 Last updated: 2013-06-10Bibliographically approved

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