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Organization of functional domains in the docking protein p130Cas
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2004 In: Biochem Biophys RES Communication, Vol. 324, no 3, 993-998 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2004. Vol. 324, no 3, 993-998 p.
URN: urn:nbn:se:uu:diva-92580OAI: oai:DiVA.org:uu-92580DiVA: diva2:165717
Available from: 2005-02-18 Created: 2005-02-18Bibliographically approved
In thesis
1. Biochemical and Structural Studies on the Adaptor Protein p130Cas
Open this publication in new window or tab >>Biochemical and Structural Studies on the Adaptor Protein p130Cas
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Crk associated substrate (Cas) is an adaptor protein that becomes phosphorylated upon integrin signaling and influences regulation of cell processes such as migration, proliferation and survival. It consists of multiple domains and regions that can interact with several signaling proteins involved in different signaling pathways. Cas was first discovered as a highly phosphorylated protein in v-Src and v-Crk transformed cells, showing involvement of this protein in cell transformation

High level of Breast cancer antiestrogen resistance protein (BCAR-1), a homologue to Cas has shown to correlate with rapid reoccurrence of breast cancer and also create resistance towards Tamoxifen, the widely used medicine for receptor positive breast cancer patients.

We have defined boundaries of two regions of Cas termed serine rich region (SRR) and Src binding domain (SBD) respectively and have isolated these segments for biochemical and structural studies. The structure of the serine rich part of Cas has been determined by NMR spectroscopy and reveals a four-helix bundle with unusually long loops. The 14-3-3 protein binds to Cas in a phospho-serine dependent manner and our study suggests that the binding site is located between two helices.

The SH2-SH3 domain of a Src family kinase, Lck has also been crystallized in complex with a nine residue long peptide corresponding to the region in Cas that binds to SH2 domains. The structure of this complex has been solved at 2.7Å and shows that Cas binds Src family kinases (SFK) with high affinity suggesting a specific interaction between these two molecules. The biochemical studies on the specific binding site of these molecules show that SFK can bind to any of the phosphorylated tyrosines on the SH2 binding domain of Cas and only one phospho-tyrosine is enough to establish the binding. This binding assay does also indicate that SH3 binding domain of Cas is not essential for SFK binding.

Place, publisher, year, edition, pages
Uppsala: Institutionen för cell- och molekylärbiologi, 2005. 50 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 10
Cell and molecular biology, Integrin signaling, p130Cas, X-ray Crystallography, NMR Spectroscopy, Protein phosphorylation, BCAR-1, Cell- och molekylärbiologi
National Category
Biochemistry and Molecular Biology
urn:nbn:se:uu:diva-4777 (URN)91-554-6143-3 (ISBN)
Public defence
2005-03-11, B42, BMC, Husargatan 3 Ingång A11, Uppsala, 10:00 (English)
Available from: 2005-02-18 Created: 2005-02-18 Last updated: 2009-06-02Bibliographically approved

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