Differential activity of c-KIT splice forms is controlled by extracellular peptide insert length |
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Authors: | Bengt Phung Eiríkur Steingrímsson Lars Rönnstrand |
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Affiliation: | 1. Experimental Clinical Chemistry, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Wallenberg Laboratory, Inga Marie Nilssons gata 53, SE-205 02 Malmö, Sweden;2. Department of Biochemistry and Molecular Biology and BioMedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavík, Iceland |
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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. |
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