Fv2 encodes a truncated form of the Stk receptor tyrosine kinase

Abstract

The Friend virus susceptibility 2 (Fv2) locus encodes a dominant host factor that confers susceptibility to Friend virus-induced erythroleukaemia in mice. We mapped Fv2 to a 1.0-Mb interval that also contained the gene (Ron) encoding the stem cell kinase receptor (Stk). A truncated form of Stk (Sf-stk), which was the most abundant form of Stk in Fv2-sensitive (Fv2ss) erythroid cells, was not expressed in Fv2 resistant (Fv2rr) cells. Enforced expression of Sf-stk conferred susceptibility to Friend disease, whereas targeted disruption of Ron caused resistance. We conclude that the Fv2 locus encodes Ron, and that a naturally expressed, truncated form of Stk confers susceptibility to Friend virus-induced erythroleukaemia.

Hypermethylation of Ron proximal promoter associates with lack of full-length Ron and transcription of oncogenic short-Ron from an internal promoter

“…For this purpose, we repeated and extended the Northern analysis to human SCLC, NSCLC and erythroleukemia cell lines (the latter included because of sfRon involvement in murine erythroleukemia, Persons et al, 1999); subsequently, we characterized the Ron protein expression and correlated both with the methylation levels of Ron proximal promoter.…”

“…Both forms of Ron were implicated in cell growth and motility, although with possible functional differences as suggested by the positive selection of both forms across evolution (murine Stk is also transcribed as a full-length and short-form, Persons et al, 1999).…”

“…In Stk a 3 bp-deletion inside intron 10 inactivates the internal promoter (Persons et al, 1999). We performed the mutation analysis of the corresponding human genomic region in several SCLC cell lines expressing sfRon and did not find mutations (data not shown).…”

“…sfStk was found expressed in animals susceptible to friend erythroleukemia virus and was absent in resistant animals, in which sfStk-enforced expression restored susceptibility (Persons et al, 1999).…”

GRB2-mediated recruitment of GAB2, but not GAB1, to SF-STK supports the expansion of Friend virus-infected erythroid progenitor cells

“…The host gene Fv2 acts in a cell autonomous manner and determines the proliferative response of infected erythroblasts to gp55 (Lilly, 1970;Behringer and Dewey, 1985). Previously, we demonstrated that Fv2 encodes the Met-related macrophagestimulating 1-receptor (Mst1r) tyrosine kinase, also known as stem cell-derived tyrosine kinase receptor (Stk) (Persons et al, 1999). Mice homozygous for the resistant allele of Fv2 (Fv2 rr ), including C57BL/6 mice, fail to express a naturally occurring, N-terminally truncated form of Stk, called short form-Stk (Sf-Stk).…”