DOMINANT-NEGATIVE EFFECTS OF A CARBOXY-TRUNCATED JAK2 MUTANT ON EPO-INDUCED PROLIFERATION AND JAK2 ACTIVATION

Members of the Janus family of protein tyrosine kinases are emerging a s primary, receptor-associated transducing factors among numerous cyto kine systems. However, little is understood regarding mechanisms of re cruitment of these kinases to receptor complexes and their ligand-depe ndent activation. To initially address these questions, we have assess ed effects of ectopically expressing a carboxy-truncated form of Jak2 (Jak2-829) in Epo-responsive DAER cells. Expression of this truncation mutant at low levels efficiently inhibited both Epo-dependent activat ion of endogenous Jak2 and Epo-induced mitogenesis (10% to 39% of pare ntal DAER cells). These results suggest that amino-terminal domains of Jak2 may mediate the assembly of Jak2/Epo receptor complexes and that integration of Jak2-829 into receptor complexes may effectively inhib it the activity of oligomeric Jak2/receptor assemblages. (C) 1994 Acad emic Press, Inc.