Differential activity of c-KIT splice forms is controlled by extracellular peptide insert length.

Summary, in English

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.

• Author: Bengt Phung; Eiríkur Steingrímsson; Lars Rönnstrand
• Department/s: Department of Translational Medicine; BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
• Publishing year: 2013
• Language: English
• Pages: 2231-2238
• Publication/Series: Cellular Signalling
• Volume: 25
• Issue: 11
• Links: http://www.ncbi.nlm.nih.gov/pubmed/23880320?dopt=Abstract; http://dx.doi.org/10.1016/j.cellsig.2013.07.011
• Document type: Journal article
• Publisher: Elsevier
• Topic: Microbiology
• Status: Published
• ISBN/ISSN/Other: ISSN: 1873-3913