Csk-binding protein mediates sequential enzymatic down-regulation and degradation of Lyn in erythropoietin-stimulated cells.
We have shown previously that the Src family kinase Lyn is involved in differentiation signals emanating from activated erythropoietin (Epo) receptors. The importance of Lyn to red cell maturation has been highlighted by Lyn-/- mice developing anemia. Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity. Intriguingly, phosphorylated Tyr314 also bound suppressor of cytokine signaling 1 (SOCS1), another well characterized negative regulator of cell signaling, resulting in elevated ubiquitination, and degradation of Lyn. In Epo-responsive primary cells and cell lines, Lyn rapidly phosphorylated Cbp, suppressing Lyn kinase activity via Csk/Ctk within minutes of Epo stimulation; hours later, SOCS1 bound to Cbp and was involved in the ubiquitination and turnover of Lyn protein. Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn.
Ingley
Evan
E
Cell Signalling Group, Western Australian Institute for Medical Research, Perth, WA 6000 Australia. eingley@waimr.uwa.edu.au
Schneider
Jessica R
JR
Payne
Christine J
CJ
McCarthy
David J
DJ
Harder
Kenneth W
KW
Hibbs
Margaret L
ML
Klinken
S Peter
SP
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D004921:Erythropoietin / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D004921:Erythropoietin; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases