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-CSF-R) leads to tyrosine-phosphorylation of multiple cytoplasmic components. To date, the kinases Jak1, Jak2, Tyk2, Lyn, and Syk have been implicated 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 responsive cells. The hematopoietic cell kinase (Hck) is a member of the Src-family of kinases known to be expressed in cells of the granulocytic 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 signaling 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 revealed recruitment of Hck to activated G-CSF-R, mediated by direct binding via its SH2 domain to multiple phosphotyrosines of the receptor. In addition, we show that Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling.
Ward
A C
AC
Institute of Hematology, Erasmus University Rotterdam, The Netherlands.ward@hema.fgg.eur.nl
Monkhouse
J L
JL
Csar
X F
XF
Touw
I P
IP
Bello
P A
PA
D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D005982:Glutathione Transferase / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000302:isolation & purification / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000302:isolation & purification / Q000378:metabolism*; D051572:Proto-Oncogene Proteins c-hck; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000302:isolation & purification / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D018909:src Homology Domains / Q000235:genetics
D011518:Proto-Oncogene Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011993:Recombinant Fusion Proteins; D016179:Granulocyte Colony-Stimulating Factor; D005982:Glutathione Transferase; D011505:Protein-Tyrosine Kinases; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck