Src-Like Adaptor Protein (SLAP) differentially regulates normal and oncogenic c-Kit signaling
Author
Summary, in English
The Src-Like Adaptor Protein (SLAP) is an adaptor protein sharing considerable structural homology with Src. SLAP is expressed in variety of cells regulating receptor tyrosine kinase signaling by direct association. In this report, we show that SLAP associates with both wild-type and oncogenic c-Kit (c-Kit-D816V). The association involves SLAP SH2 domain and receptor phosphotyrosine residues different from those mediating Src interaction. Association of SLAP triggers c-Kit ubiquitination which, in turn, is followed by receptor degradation. Although SLAP depletion potentiates c-Kit downstream signaling by stabilizing the receptor, it remains non-functional in c-Kit-D816V signaling. Ligand-stimulated c-Kit or c-Kit-D816V did not alter membrane localization of SLAP. Interestingly oncogenic c-Kit-D816V, but not wild-type c-Kit, phosphorylates SLAP on Y120, Y258 and Y273 residues. Physical interaction between c-Kit-D816V and SLAP is mandatory for the phosphorylation to take place. Although tyrosine phosphorylated SLAP does not affect c-Kit-D816V signaling, mutation of these tyrosine sites to phenylalanine can restore SLAP activity. Taken together the data demonstrate that SLAP negatively regulates wild-type c-Kit signaling, but not its oncogenic counterpart, indicating a possible mechanism by which the oncogenic c-Kit bypasses the normal cellular negative feedback control.
Department/s
- Molecular Cancer Research
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- Department of Translational Medicine
Publishing year
2014
Language
English
Pages
653-662
Publication/Series
Journal of Cell Science
Volume
127
Issue
3
Full text
Links
Document type
Journal article
Publisher
The Company of Biologists Ltd
Topic
- Medicinal Chemistry
Keywords
- Kit
- c-Kit-D816V
- D816V
- Receptor tyrosine kinase
- Signal transduction
- SLA
- Ubiquitylation
Status
Published
Research group
- Molecular Cancer Research
ISBN/ISSN/Other
- ISSN: 0021-9533