I. Devivo et al., GROWTH-STIMULATION OF PRIMARY B-CELL PRECURSORS BY THE ANTI-PHOSPHATASE SBF1, Proceedings of the National Academy of Sciences of the United Statesof America, 95(16), 1998, pp. 9471-9476
SET binding factor 1 (Sbf1) was originally discovered by virtue of its
interaction with a highly conserved motif (the SET domain) of unknown
function in the protoon-coprotein homolog of Drosophila trithorax, Hr
x, Sbf1 shares extensive sequence similarity with myotubularin, a dual
specificity phosphatase (dsPTPase) that is mutated in a subset of pat
ients with inherited myopathies. Both Sbf1 and myotubularin interact w
ith the SET domains of Hrx and other epigenetic regulatory proteins, b
ut Sbf1 lacks phosphatase activity due to several evolutionarily conse
rved amino acid changes in its structurally preserved catalytic pocket
, Thus, Sbf1 has features of an anti-phosphatase that could competitiv
ely antagonize dsPTPases; however the in vivo role for such factors re
mains unknown, Given its ability to physically interact with Hrx, a de
velopmental regulator subject to translocation-induced mutations in B
cell precursor leukemias, the current studies were undertaken to asses
s the effects of Sbf1 on lymphopoiesis, After infection with recombina
nt Sbf1 retroviruses, bone marrow cells were plated under Whitlock-Wit
te conditions for long-term culture of B lineage cells, Sbf1-expressin
g cells rapidly dominated the cultures resulting in clonal outgrowths
of B cell progenitors that retained a dependence on their primary bone
marrow-derived stroma for continuous growth in vitro, Structure/funct
ion analyses demonstrated that the SET interaction domain of Sbf1 was
necessary and sufficient for growth alterations of B cell progenitors.
These observations support a model in which Sbf1 functions as a SET d
omain-dependent positive regulator of growth-inducing kinase signaling
pathways that impinge on SET domain proteins. SET domain-dsPTPase int
eractions appear to be critically important for regulating the growth
properties of B cell progenitors.