THE SRC-LIKE TYROSINE KINASE HCK IS ACTIVATED BY GRANULOCYTE-COLONY-STIMULATING FACTOR (G-CSF) AND DOCKS TO THE ACTIVATED G-CSF RECEPTOR

Activation of the granulocyte colony-stimulating factor receptor (G-CS F-R) leads to tyrosine-phosphorylation of multiple cytoplasmic compone nts. To date, the kinases Jak1, Jak2, Tyk2, Lyn, and Syk have been imp licated in this process. However, it is unknown if other kinases might be involved in the diverse responses from the G-CSF-R, which include mitogenesis, survival, differentiation, and functional activation of r esponsive cells. The hematopoietic cell kinase (Hck) is a member of th e Src-family of kinases known to be expressed in cells of the granuloc ytic Lineage. It also interacts with the gp130 subunit of the LIF/IL-6 receptors, which is closely related to the G-CSF-R, and so represents a good candidate for mediating at least some of the downstream signal ing from the G-CSF-R. Therefore, we investigated the activation of Hck by the G-CSF-R in intact cells as well as in vitro. These studies rev ealed recruitment of Hck to activated G-CSF-R, mediated by direct bind ing via its SH2 domain to multiple phosphotyrosines of the receptor. I n addition, we show that Hck becomes activated upon G-CSF treatment an d is, in turn, able to phosphorylate the G-CSF-R, indicating a clear f unctional and physical involvement in G-CSF signaling. (C) 1998 Academ ic Press.