Characterization of the Kaposi's sarcoma-associated herpesvirus K1 signalosome.
Kaposi's sarcoma (KS) is a multifocal angiogenic tumor and appears to be a hyperplastic disorder caused, in part, by local production of inflammatory cytokines. The K1 lymphocyte receptor-like protein of KS-associated herpesvirus (KSHV) efficiently transduces extracellular signals to elicit cellular activation events through its cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM). To further delineate K1-mediated signal transduction, we purified K1 signaling complexes and identified its cellular components. Upon stimulation, the K1 ITAM was efficiently tyrosine phosphorylated and subsequently interacted with cellular Src homology 2 (SH2)-containing signaling proteins Lyn, Syk, p85, PLCgamma2, RasGAP, Vav, SH2 domain-containing protein tyrosine phosphatase 1/2, and Grab2 through its phosphorylated tyrosine residues. Mutational analysis demonstrated that each tyrosine residue of K1 ITAM contributed to the interactions with cellular signaling proteins in distinctive ways. Consequently, these interactions led to the marked augmentation of cellular signal transduction activity, evidenced by the increase of cellular tyrosine phosphorylation and intracellular calcium mobilization, the activation of NF-AT and AP-1 transcription factor activities, and the production of inflammatory cytokines. These results demonstrate that KSHV K1 effectively recruits a set of cellular SH2-containing signaling molecules to form the K1 signalosome, which elicits downstream signal transduction and induces inflammatory cytokine production.
Lee
Bok-Soo
BS
Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan City, Chonbuk, Korea.
Lee
Sun-Hwa
SH
Feng
Pinghui
P
Chang
Heesoon
H
Cho
Nam-Hyuk
NH
Jung
Jae U
JU
D020816:Amino Acid Motifs; D002118:Calcium / Q000032:analysis; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000032:analysis; D003593:Cytoplasm / Q000737:chemistry; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D004792:Enzyme Precursors / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011485:Protein Binding; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction; D000072377:Syk Kinase; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
D018797:Cell Cycle Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; C111600:K1 protein, Human herpesvirus 8; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C496618:VAV1 protein, human; D014764:Viral Proteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium