title: Src-like-adaptor protein (SLAP) differentially regulates normal and oncogenic c-Kit signaling.
abstract: The Src-like-adaptor protein (SLAP) is an adaptor protein sharing considerable structural homology with Src. SLAP is expressed in a variety of cells and regulates 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 the SLAP SH2 domain and receptor phosphotyrosine residues different from those mediating Src interaction. Association of SLAP triggers c-Kit ubiquitylation 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 residues Y120, Y258 and Y273. 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.
authors.affiliation: Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, 22381 Lund, Sweden.
authors.forename: Julhash U
authors.initials: JU
authors.lastname: Kazi
authors.forename: Shruti
authors.initials: S
authors.lastname: Agarwal
authors.forename: Jianmin
authors.initials: J
authors.lastname: Sun
authors.forename: Enrico
authors.initials: E
authors.lastname: Bracco
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnstrand
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D010766:Phosphorylation; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D018909:src Homology Domains / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490635:SLA protein, human; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit; D016392:Proto-Oncogene Proteins pp60(c-src)
keywords: D816V; Kit; Receptor tyrosine kinase; SLA; Signal transduction; Ubiquitylation; c-Kit-D816V