Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling.
Suppressor of cytokine signaling (SOCS) proteins are a family of Src homology 2-containing adaptor proteins. Cytokine-inducible Src homology domain 2-containing protein, SOCS1, SOCS2, and SOCS3 have been implicated in the down-regulation of cytokine signaling. The function of SOCS4, 5, 6, and 7 are not known. KIT receptor signaling is regulated by protein tyrosine phosphatases and adaptor proteins. We previously reported that SOCS1 inhibited cell proliferation in response to stem cell factor (SCF). By screening the other members of SOCS family, we identified SOCS6 as a KIT-binding protein. Using KIT mutants and peptides, we demonstrated that SOCS6 bound directly to KIT tyrosine 567 in the juxtamembrane domain. To investigate the function of this interaction, we constitutively expressed SOCS6 in cell lines. Ectopic expression of SOCS6 in Ba/F3-KIT cell line decreased cell proliferation in response to SCF but not SCF-induced chemotaxis. SOCS6 reduced SCF-induced activation of ERK1/2 and p38 but not activation of AKT or STATs in Ba/F3, murine embryonic fibroblast (MEF), or COS-7 cells. SOCS6 did not impair ERK and p38 activation by other stimuli. These results indicate that SOCS6 binds to KIT juxtamembrane region, which affects upstream signaling components leading to MAPK activation. Our results indicate that KIT signaling is regulated by several SOCS proteins and suggest a putative function for SOCS6 as a negative regulator of receptor tyrosine kinases.
Bayle
Julie
J
Institut National de la Santé et de la Recherche Médicale (INSERM) U119, Laboratoire d'Hématopoïèse Moléculaire et Fonctionnelle, 27 Boulevard Lei Roure, 13009 Marseille, France.
Letard
Sébastien
S
Frank
Ronald
R
Dubreuil
Patrice
P
De Sepulveda
Paulo
P
D000595:Amino Acid Sequence; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D019556:COS Cells; D002455:Cell Division; D002460:Cell Line; D002465:Cell Movement; D002633:Chemotaxis; D015536:Down-Regulation; D004789:Enzyme Activation; D005982:Glutathione Transferase / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins; D013997:Time Factors; D020798:Two-Hybrid System Techniques; D014443:Tyrosine / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases; D018909:src Homology Domains
D010455:Peptides; D011506:Proteins; D011993:Recombinant Fusion Proteins; C473085:SOCS6 protein, human; D019089:Stem Cell Factor; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine; D000841:Anisomycin; D005982:Glutathione Transferase; D019009:Proto-Oncogene Proteins c-kit; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases