RanBPM (RanBP9) regulates mouse c-Kit receptor level and is essential for normal development of bone marrow progenitor cells

// Sandrine Puverel 1, * , Erkan Kiris 1, * , Satyendra Singh 1 , Kimberly D. Klarmann 1, 2 , Vincenzo Coppola 3 , Jonathan R. Keller 1, 2 , Lino Tessarollo 1 1 Mouse Cancer Genetics Program, Center for Cancer Research, NCI, Frederick, MD 21702, USA 2 Basic Science Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, NCI, Frederick, MD 21702, USA 3 The Ohio State University, Department of Cancer, Biology and Genetics, Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA * These authors have contributed equally to this work Correspondence to: Lino Tessarollo, email: tessarol@mail.nih.gov Keywords: RanBP9, c-Kit signaling, hematopoietic system, spermatogenesis, stem cells Received: April 19, 2016      Accepted: October 26, 2016      Published: November 08, 2016 ABSTRACT 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.