Ankyrin repeat and suppressors of cytokine signaling box protein asb-9 targets creatine kinase B for degradation.
The suppressors of cytokine signaling (SOCS) proteins inhibit cytokine action by direct interaction with Janus kinases or activated cytokine receptors. In addition to the N-terminal and Src homology 2 domains that mediate these interactions, SOCS proteins contain a C-terminal SOCS box. DNA data base searches have identified a number of other protein families that possess a SOCS box, of which the ankyrin repeat and SOCS box-containing (Asb) proteins constitute the largest. Although it is known that the SOCS proteins are involved in the negative regulation of cytokine signaling, the biological and biochemical functions of the Asbs are largely undefined. Using a proteomics approach, we demonstrate that creatine kinase B (CKB) interacts with Asb-9 in a specific, SOCS box-independent manner. This interaction increases the polyubiquitylation of CKB and decreases total CKB levels within the cell. The targeting of CKB for degradation by Asb-9 was primarily SOCS box-dependent and suggests that Asb-9 acts as a specific ubiquitin ligase regulating levels of this evolutionarily conserved enzyme.
Debrincat
Marlyse A
MA
Division of Cancer and Haematology and, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia; Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
Zhang
Jian-Guo
JG
Division of Cancer and Haematology and, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia; Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Willson
Tracy A
TA
Division of Cancer and Haematology and, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia; Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Silke
John
J
Department of Biochemistry, R. L. Reid Building, La Trobe University, Bundoora, Victoria 3086, Australia, and the.
Connolly
Lisa M
LM
The Joint Proteomics Laboratory of the Walter and Eliza Hall Institute and Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
Simpson
Richard J
RJ
The Joint Proteomics Laboratory of the Walter and Eliza Hall Institute and Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
Alexander
Warren S
WS
Division of Cancer and Haematology and, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Nicola
Nicos A
NA
Division of Cancer and Haematology and, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Kile
Benjamin T
BT
Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Hilton
Douglas J
DJ
Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. Electronic address: hilton@wehi.edu.au.
D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D030562:Databases, Protein; D019143:Evolution, Molecular; D006801:Humans; D051379:Mice; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D040901:Proteomics; D015398:Signal Transduction / Q000502:physiology; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D018909:src Homology Domains / Q000502:physiology
D017487:Ankyrins; C518251:Asb9 protein, mouse; D016207:Cytokines; D050826:Suppressor of Cytokine Signaling Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D003402:Creatine Kinase