RanBPM (RanBP9) regulates mouse c-Kit receptor level and is essential for normal development of bone marrow progenitor cells
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Sandrine Puverel1,*, Erkan Kiris1,*, Satyendra Singh1, Kimberly D. Klarmann1,2, Vincenzo Coppola3, Jonathan R. Keller1,2, Lino Tessarollo1
1Mouse Cancer Genetics Program, Center for Cancer Research, NCI, Frederick, MD 21702, USA
2Basic Science Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, NCI, Frederick, MD 21702, USA
3The 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
Lino Tessarollo, email: [email protected]
Keywords: RanBP9, c-Kit signaling, hematopoietic system, spermatogenesis, stem cells
Received: April 19, 2016 Accepted: October 26, 2016 Published: November 08, 2016
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.
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