Activation of JAK2 in human vascular endothelial cells by granulocyte-macrophage colony-stimulating factor.
Besides the regulation of hematopoiesis, granulocyte-macrophage colony-stimulating factor (GM-CSF)induces the expression of a functional program in endothelial cells (ECs) related to angiogenesis and to their survival in the bone marrow microenvironment. ECs express specific GM-CSF high-affinity binding sites, which mediate the proliferative and migratory response. We now report that ECs express the alpha and beta subunits of GM-CSF receptor (GM-CSFR), and that GM-CSF is able to activate the Janus kinase (JAK)2, a member of the cytosolic tyrosine kinase family, which is known to mediate signals of several non-tyrosine kinase receptors. JAK2 tyrosine phosphorylation, as well as activation of its catalytic activity, is induced by subnanomolar concentrations of GM-CSF and occurs within 3 minutes of stimulation and persists at least for 10 minutes. The effect is specific as inferred by the lack of effect of heat-inactivated GM-CSF or neutralized by specific antibodies and by the finding that interleukin-5, which utilizes a specific alpha chain and the same beta chain of GM-CSFR, does not phosphorylate JAK2. Furthermore, we show that the amount of JAK2 physically associated with GM-CSFR beta chain is increased after GM-CSF stimulation and that GM-CSF triggers both beta chain and JAK2 tyrosine phosphorylation. Taken together, these results suggest that biologic activities of GM-CSF in vascular endothelium may, in part, be elicited by GM-CSFR-mediated JAK2 activation.
Soldi
R
R
Dipartimento di Genetica, Biologia e Chimica Medica, Torino, Italy.
Primo
L
L
Brizzi
M F
MF
Sanavio
F
F
Aglietta
M
M
Polentarutti
N
N
Pegoraro
L
L
Mantovani
A
A
Bussolino
F
F
D004730:Endothelium, Vascular / Q000201:enzymology* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D053614:Janus Kinase 2; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000032:analysis / Q000096:biosynthesis; D014471:Umbilical Veins
D011518:Proto-Oncogene Proteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D019000:Phosphotyrosine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2