Identification and functional characterization of an Src homology domain 3 domain-binding site on Cbl.

Identification and functional characterization of an Src homology domain 3 domain-binding site on Cbl. Research Abstract Details 

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Identification and functional characterization of an Src homology domain 3 domain-binding site on Cbl. Abstract Text:

Archana Sanjay,Tsuyoshi Miyazaki,Cecile Itzstein,Enkhtsetseg Purev,William C Horne,Roland Baron,

Cbl is an adaptor protein and ubiquitin ligase that binds and is phosphorylated by the nonreceptor tyrosine kinase Src. We previously showed that the primary interaction between Src and Cbl is mediated by the Src homology domain 3 (SH3) of Src binding to proline-rich sequences of Cbl. The peptide Cbl RDLPPPPPPDRP(540-551), which corresponds to residues 540-551 of Cbl, inhibited the binding of a GST-Src SH3 fusion protein to Cbl, whereas RDLAPPAPPPDR(540-551) did not, suggesting that Src binds to this site on Cbl in a class I orientation. Mutating prolines 543-548 reduced Src binding to the Cbl 479-636 fragment significantly more than mutating the prolines in the PPVPPR(494-499) motif, which was previously reported to bind Src SH3. Mutating Cbl prolines 543-548 to alanines substantially reduced Src binding to Cbl, Src-induced phosphorylation of Cbl, and the inhibition of Src kinase activity by Cbl. Expressing the mutated Cbl in osteoclasts induced a moderate reduction in bone-resorbing activity and increased amounts of Src protein. In contrast, disabling the tyrosine kinase-binding domain of full-length Cbl by mutating glycine 306 to glutamic acid, and thereby preventing the previously described binding of the tyrosine kinase-binding domain to the Src phosphotyrosine 416, had no effect on Cbl phosphorylation, the inhibition of Src activity by full-length Cbl, or bone resorption. These data indicate that the Cbl RDLPPPP(540-546) sequence is a functionally important binding site for Src.

Identification and functional characterization of an Src homology domain 3 domain-binding site on Cbl. Publishing Authors By Initials

A Sanjay,T Miyazaki,C Itzstein,E Purev,WC Horne,R Baron,

For similar biochemical phenomena, metabolism, and nutrition: biochemical phenomena: molecular structure: molecular conformation: protein conformation: protein structure, tertiary: protein interaction domains and motifs: src homology domains research abstracts see: biochemical phenomena, metabolism, and nutrition: biochemical phenomena: molecular structure: molecular conformation: protein conformation: protein structure, tertiary: protein interaction domains and motifs: src homology domains research

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Identification and functional characterization of an Src homology domain 3 domain-binding site on Cbl. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The FEBS journal

VOLUME: 273

Page Numbers: 5442-56

Journal Abbreviation: FEBS J.

ISSN: 1742-464X

DAY: 9

MONTH: 11

YEAR: 2006

Identification and functional characterization of an Src homology domain 3 domain-binding site on Cbl. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 101229646

Identification and functional characterization of an Src homology domain 3 domain-binding site on Cbl. Keywords Mesh Terms:

KEYWORDS: src Homology Domains

MESH TERMS: metabolism

Chemical & Substance for Abstract: Identification and functional characterization of an Src homology domain 3 domain-binding site on Cbl. Information

Substance Name: Proto-Oncogene Proteins c-cbl

Registry Number: EC 6.3.2.-

Grant and Affiliation Information for Identification and functional characterization of an Src homology domain 3 domain-binding site on Cbl.

AFFILIATION: Departments of Orthopedics & Rehabilitation and Cell Biology, Yale University School of Medicine, New Haven, CT, USA.

Country: England

AGENCY: United States NIDCR

GRANT: DE-04724

ACRONYM: DE

MEDLINETA: FEBS J

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