RanBPM (RanBP9) regulates mouse c-Kit receptor level and is essential for normal development of bone marrow progenitor cells.
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.
Mouse Cancer Genetics Program, Center for Cancer Research, NCI, Frederick, MD 21702, USA.
Sandrine
S
Puverel
Mouse Cancer Genetics Program, Center for Cancer Research, NCI, Frederick, MD 21702, USA.
Erkan
E
Kiris
Mouse Cancer Genetics Program, Center for Cancer Research, NCI, Frederick, MD 21702, USA.
Satyendra
S
Singh
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.
Kimberly D
KD
Klarmann
The Ohio State University, Department of Cancer, Biology and Genetics, Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA.
Vincenzo
V
Coppola
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.
Jonathan R
JR
Keller
Mouse Cancer Genetics Program, Center for Cancer Research, NCI, Frederick, MD 21702, USA.
Lino
L
Tessarollo
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005854:Germ Cells / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D013737:Testis / Q000473:pathology*
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C116005:Ran binding protein 9; D019009:Proto-Oncogene Proteins c-kit
RanBP9; c-Kit signaling; hematopoietic system; spermatogenesis; stem cells