Puverel Sandrine, Kiris Erkan, Singh Satyendra, Klarmann Kimberly D, Coppola Vincenzo, Keller Jonathan R, Tessarollo Lino
Mouse Cancer Genetics Program, Center for Cancer Research, NCI, Frederick, MD 21702, USA.
Basic Science Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, NCI, Frederick, MD 21702, USA.
Oncotarget. 2016 Dec 20;7(51):85109-85123. doi: 10.18632/oncotarget.13198.
c-Kit is a tyrosine kinase receptor important for gametogenesis, hematopoiesis, melanogenesis and mast cell biology. Dysregulation of c-Kit function is oncogenic and its expression in the stem cell niche of a number of tissues has underlined its relevance for regenerative medicine and hematopoietic stem cell biology. Yet, very little is known about the mechanisms that control c-Kit protein levels. Here we show that the RanBPM/RanBP9 scaffold protein binds to c-Kit and is necessary for normal c-Kit protein expression in the mouse testis and subset lineages of the hematopoietic system. RanBPM deletion causes a reduction in c-Kit protein but not its mRNA suggesting a posttranslational mechanism. This regulation is specific to the c-Kit receptor since RanBPM reduction does not affect other membrane proteins examined. Importantly, in both mouse hematopoietic system and testis, RanBPM deficiency causes defects consistent with c-Kit loss of expression suggesting that RanBPM is an important regulator of c-Kit function. The finding that this regulatory mechanism is also present in human cells expressing endogenous RanBPM and c-Kit suggests a potential new strategy to target oncogenic c-Kit in malignancies.
c-Kit是一种酪氨酸激酶受体，对配子发生、造血、黑色素生成和肥大细胞生物学非常重要。c-Kit功能失调具有致癌性，其在许多组织的干细胞微环境中的表达突出了其与再生医学和造血干细胞生物学的相关性。然而，对于控制c-Kit蛋白水平的机制知之甚少。在这里，我们表明RanBPM/RanBP9支架蛋白与c-Kit结合，并且是小鼠睾丸和造血系统亚群谱系中正常c-Kit蛋白表达所必需的。RanBPM缺失导致c-Kit蛋白减少，但不影响其mRNA，提示存在翻译后机制。这种调节对c-Kit受体具有特异性，因为RanBPM减少不影响所检测的其他膜蛋白。重要的是，在小鼠造血系统和睾丸中，RanBPM缺乏都会导致与c-Kit表达缺失一致的缺陷，这表明RanBPM是c-Kit功能的重要调节因子。在表达内源性RanBPM和c-Kit的人类细胞中也存在这种调节机制的发现，提示了一种针对恶性肿瘤中致癌性c-Kit的潜在新策略。
