CARBOXYL-TRUNCATED STAT5-BETA IS GENERATED BY A NUCLEUS-ASSOCIATED SERINE-PROTEASE IN EARLY HEMATOPOIETIC PROGENITORS

Hematopoiesis is tightly controlled by a family of cytokines that sign al 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 intere st is STAT5, which is stimulated by a large and diverse set of cytokin es. In addition to the two highly homologous proteins, STAT5A and STAT 5B, encoded by duplicated genes, expression and activation of a domina nt-negative, carboxyl-truncated form has also been described in early hematopoietic progenitors, We show here that a protease expressed in e arly hematopoietic cells cleaves the alpha forms of STAT5A/5B (p96/p94 ) to generate carboxyl-truncated beta forms (p80/p77). Inhibition stud ies 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 a n activated STAT5 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 function s. (C) 1998 by The American Society of Hematology.