Growth factor pleiotropy is controlled by a receptor Tyr/Ser motif that acts as a binary switch.
Pleiotropism is a hallmark of cytokines and growth factors; yet, the underlying mechanisms are not clearly understood. We have identified a motif in the granulocyte macrophage-colony-stimulating factor receptor composed of a tyrosine and a serine residue that functions as a binary switch for the independent regulation of multiple biological activities. Signalling occurs either through Ser585 at lower cytokine concentrations, leading to cell survival only, or through Tyr577 at higher cytokine concentrations, leading to cell survival as well as proliferation, differentiation or functional activation. The phosphorylation of Ser585 and Tyr577 is mutually exclusive and occurs via a unidirectional mechanism that involves protein kinase A and tyrosine kinases, respectively, and is deregulated in at least some leukemias. We have identified similar Tyr/Ser motifs in other cell surface receptors, suggesting that such signalling switches may play important roles in generating specificity and pleiotropy in other biological systems.
Guthridge
Mark A
MA
Cytokine Receptor Laboratory, Department of Human Immunology, Institute of Medical and Veterinary Science, Hanson Institute, Adelaide, SA, Australia.
Powell
Jason A
JA
Barry
Emma F
EF
Stomski
Frank C
FC
McClure
Barbara J
BJ
Ramshaw
Hayley
H
Felquer
Fernando A
FA
Dottore
Mara
M
Thomas
Daniel T
DT
To
Bik
B
Begley
C Glenn
CG
Lopez
Angel F
AF
D048948:14-3-3 Proteins / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010766:Phosphorylation; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D048948:14-3-3 Proteins; D039481:CD11b Antigen; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D014443:Tyrosine; D012694:Serine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017868:Cyclic AMP-Dependent Protein Kinases