Active mutations in KIT tyrosine kinase, a signalling receptor protein that plays a crucial role in the growth and survival of different types of cells, are found in several cancers such as acute myeloid leukemia (AML). However, it remains unclear whether KIT transduces cancer-specific signals from intracellular compartments of AML cells. One of the major active KIT mutations in AML is N822K, however, the signalling platform and mechanisms of N822K are relatively unknown. Scientists from Japan funded by AMED* investigated the relationship between the localisation of KITN822K (KIT protein carrying the N822K mutation) and its activation in an AML cell line. Scientists found that in AML cells, KITN822K mislocalised to, and accumulated in the endolysosome. Using immunofluorescence experiments they showed that KIT was activated in the Golgi, a finding observed in other leukemia cells that have KIT mutations. Additionally, when they treated cells with brefeldin A (BFA) or 2-methylcoprophilinamide (M-COPA), compounds that block intracellular transport of proteins, KIT was retained in the ER. This also decreased the auto-phosphorylation of KIT and thereby its downstream signalling. Where as suppression of Golgi export of KIT using monensin did not suppress the KIT signals, which told the scientists that mutated KIT carries out cancer signalling specifically at the Golgi.
So, what are the future applications of this study? Small molecule tyrosine kinase inhibitors and antibodies against receptor tyrosine kinases have been developed to suppress cancer proliferative signalling using mechanisms similar to the ones described above. According to Prof. Shiina (co-author of the research article, based at TUS#), this study reveals that the novel compound M-COPA can be used to block transport of KIT from the ER to the Golgi (where it is activated and carries out downstream oncogenic signalling). The scientists say that the compound M-COPA has applications such as treatment of patients with AML, improved prognosis for these patients, and improvement in the quality of life of these patients. Prof. Shiina concludes by stating, “Currently, the synthesis of various M-COPA analogs is progressing every day at our university, and their inhibitory effects against hematological cancers and solid cancers (stomach cancer, lung cancer, ovarian cancer, etc.) are being verified.”
Journal Article: Obata et al., 2019. N822K- or V560G-mutated KIT activation preferentially occurs in lipid rafts of the Golgi apparatus in leukemia cells. Cell Communication and Signaling
Article provided by Indrani Das, summarised by Cheleka Mpande
#About The Tokyo University of Science
Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan’s development in science through inculcating the love for science in researchers, technicians, and educators.
With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society”, TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today’s most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.
*About The Japan Agency for Medical Research and Development (AMED)
AMED was established in 2015 for the advancement of medical discoveries that make life better for everyone. AMED’s mission is to fast-track medical R&D with an alliance and cooperativity of the ministries (CAO, METI, MEXT and MHLW). AMED provides seamless support on medical research, from basic research to clinical applications, by centralizing grants in the field of medicine. Based on effective partnerships and innovative collaboration, AMED pursues medical breakthroughs through an approach consisting of three vital components; Funding for medical studies and research facilities, Linking organizations, institutions and researchers, and Promotion for the practical application of beneficial research outcomes.