Carboxyl-truncated STAT5β is generated by a nucleus-associated serine protease in early hematopoietic progenitors

Abstract

Hematopoiesis is tightly controlled by a family of cytokines that signal through a related set of receptors. The pleiotropic and overlapping response of a cell to different cytokines is reflected in the number and complex pattern of activated signal transducers. Of special interest is STATS, which is stimulated by s large end diverse set of cytokines. In addition to the two highly homologous proteins, STAT5A end STAT5B, encoded by duplicated genes, expression and activation of a dominant-negative, carboxyl-truncated form has also been described in early hematopoietic progenitors. We show here that a protease expressed in early hematopoietic cells cleaves the α forms of STAT5A/5B (p96/p94) to generate carboxyl-truncated p forms (p80/p77). Inhibition studies assigned this protease to the serine class of endopeptidases. Cell fractionation experiments showed that the protease is associated with the nucleus in a constitutively activated form and does not require an activated STATS substrate. The ability of a protease to modulate the specificity of an activated transcription factor is unprecedented and underlines the importance of proteases in regulation of cell functions.