title: Suppressor of cytokine signaling 1 interacts with oncogenic lymphocyte-specific protein tyrosine kinase.
abstract: Lymphocyte-specific protein tyrosine kinase (Lck) plays a key role in T cell signal transduction and is tightly regulated by phosphorylation and dephosphorylation. Lck can function as an oncoprotein when overexpressed or constantly activated by mutations. Our previous studies showed that Lck-induced cellular transformation could be suppressed by enforced expression of suppressor of cytokine signaling 1 (SOCS1), a SOCS family member involved in the negative feedback control of cytokine signaling. We observed attenuated Lck kinase activity in SOCS1-expressing cells, suggesting an important role of SOCS in regulating Lck functions. It remains largely unknown whether and how SOCS proteins interact with the oncogenic Lck kinase. Here, we report that among four SOCS family proteins, SOCS1, SOCS2, SOCS3 and CIS (cytokine-inducible SH2 domain containing protein), SOCS1 has the highest affinity in binding to the oncogenic Lck kinase. We identified the positive regulatory phosphotyrosine 394 residue in the kinase domain as the key interacting determinant in Lck. Additionally, the Lck kinase domain alone is sufficient to bind SOCS1. While the SH2 domain in SOCS1 is important in its association with the oncogenic Lck kinase, other functional domains may also contribute to overall binding affinity. These findings provide important mechanistic insights into the role of SOCS proteins as tumor suppressors in cells transformed by oncogenic protein tyrosine kinases.
authors.affiliation: Department of Microbiology and Immunology, H. M. Bligh Cancer Research Laboratories, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
authors.forename: Srividya
authors.initials: S
authors.lastname: Venkitachalam
authors.forename: Fu-Yu
authors.initials: FY
authors.lastname: Chueh
authors.forename: King-Fu
authors.initials: KF
authors.lastname: Leong
authors.forename: Samantha
authors.initials: S
authors.lastname: Pabich
authors.forename: Chao-Lan
authors.initials: CL
authors.lastname: Yu
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010770:Phosphotransferases / Q000737:chemistry / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D025941:Protein Interaction Mapping; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014443:Tyrosine / Q000235:genetics
chemical_list: D015513:Oncogene Proteins; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine; D010770:Phosphotransferases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)