CrkL and CrkII participate in the generation of the growth inhibitory effects of interferons on primary hematopoietic progenitors

Interferons are potent regulators of normal and malignant hematopoietic cel l proliferation in vitro and in vivo, but the signaling mechanisms by which they exhibit their growth inhibitory effects are unknown. We have recently shown that CrkL is engaged in Type I IFN signaling, as shown by its rapid tyrosine phosphorylation during engagement of the Type I IFN receptor. In t he present study, we provide evidence that the related CrkII protein is als o rapidly phosphorylated on tyrosine during treatment of U-266 and Daudi ce lls with INF alpha or IFN beta. We also show that both members of the Crk-f amily, CrkL and CrkII, are phosphorylated in an interferon-dependent manner in primary hematopoietic progenitors. Furthermore, inhibition of CrkL or C rkII protein expression by antisense oligonucleotides, reverses the inhibit ory effects of IFN alpha or IFN gamma on the proliferation of normal bone m arrow progenitor cells (colony forming units-granulocytic/monocytic [CFU-GM ] and burst-forming units-erythroid [BFU-E]). Thus, both CrkL and CrkII are engaged in a signaling pathway (s) that mediates interferon-regulated inhi bition of hematopoietic cell proliferation, (C) 1999 International Society for Experimental Hematology, published by Elsevier Science Inc.