title: Differential activity of c-KIT splice forms is controlled by extracellular peptide insert length.
abstract: Understanding receptor activation is important for disease intervention. Activation of the receptor tyrosine kinase c-KIT is involved in numerous diseases including melanoma, mastocytosis, multiple myeloma and gastrointestinal stromal tumors. To better understand the regulation of activation, we studied the two c-KIT isoforms, c-KIT(-) and c-KIT(+), which differ by a tetrapeptide insert GNNK, located in the extracellular juxtamembrane domain of the c-KIT(+) isoform. This region is important for regulating receptor activation. Here we show that the consecutive elimination of one amino acid at a time from the GNNK tetrapeptide insert gradually increases receptor tyrosine phosphorylation, ubiquitination, internalization and downstream MAP kinase-ERK activation. Successively decreasing the insert length progressively improves cell survival during drug treatment. Our results indicate that the length of the tetrapeptide fine-tunes receptor activity, thus providing deeper insight into c-KIT activation.
authors.affiliation: Experimental Clinical Chemistry, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Wallenberg Laboratory, Inga Marie Nilssons gata 53, SE-205 02 Malmö, Sweden. bengt.phung@med.lu.se
authors.forename: Bengt
authors.initials: B
authors.lastname: Phung
authors.forename: Eiríkur
authors.initials: E
authors.lastname: Steingrímsson
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnstrand
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D020033:Protein Isoforms; D019009:Proto-Oncogene Proteins c-kit; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Growth factor receptor; Melanoma survival; Pigment synthesis; Receptor kinase rotation; Splice form; Stem cell factor