Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling.
Suppressors of cytokine signaling (SOCS) are Src homology-2-containing proteins originally identified as negative regulators of cytokine signaling. Accumulating evidence indicates a role for SOCS proteins in the regulation of additional signaling pathways including receptor tyrosine kinases. Notably, SOCS36E, the Drosophila ortholog of mammalian SOCS5, was recently implicated as a negative regulator of the Drosophila ortholog of EGFR. In this study, we aimed at characterizing the role of SOCS5 in the negative regulation of EGFR. Here we show that the expression of SOCS5 and its closest homolog SOCS4 is elevated in cells following treatment with EGF, similar to several negative feedback regulators of EGFR whose expression is up-regulated upon receptor activation. The expression of SOCS5 led to a marked reduction in EGFR expression levels by promoting EGFR degradation. The reduction in EGFR levels and EGF-induced signaling in SOCS5-expressing cells requires both the Src homology-2 and SOCS box domains of SOCS5. Interestingly, EGFR is degraded by SOCS5 prior to EGF treatment in a ligand- and c-Cbl-independent manner. SOCS5 can associate with EGFR and can also bind the ElonginBC protein complex via its SOCS box, which may recruit an E3 ubiquitin ligase to promote EGFR degradation. Thus, we have characterized a novel function for SOCS5 in regulating EGFR and discuss its potential role in controlling EGFR homeostasis.
Kario
Edith
E
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, 76100, Israel.
Marmor
Mina D
MD
Adamsky
Konstantin
K
Citri
Ami
A
Amit
Ido
I
Amariglio
Ninette
N
Rechavi
Gideon
G
Yarden
Yosef
Y
D000818:Animals; D002460:Cell Line; D000075065:Elongin; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D000075065:Elongin; D011506:Proteins; C473084:SOCS4 protein, human; C408990:SOCS5 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors