期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 101, 期 50, 页码 17416-17421出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0408061101
关键词
NF-kappa B; serine phosphorylation; cell migration
资金
- NCI NIH HHS [R01 CA047006, R01 CA085180, R35 CA047006, CA 85180, CA 47006] Funding Source: Medline
Dok1 is an abundant Ras-GTPase-activating protein-associated tyrosine kinase substrate that negatively regulates cell growth and promotes migration. We now find that lkappaB kinase beta (IKKbeta) associated with and phosphorylated Dok1 in human epithelial cells and B lymphocytes. IKKbeta phosphorylation of Dok1 depended on Dok1 S-439, S-443, S-446, and S-450. Recombinant IKKbeta also phosphorylated Dok1 or Dok1 amino acids 430-481 in vitro. TNF-alpha, IL-1, gamma radiation, or IKKbeta overexpression phosphorylated Dok1 S-443, S-446, and S-450 in vivo, as detected with Dok1 phospho-S site-specific antisera. Moreover, Dokl with 5439, 5443, 5446, and 5450 mutated to A was not phosphorylated by IKKbeta in vivo. Surprisingly, mutant Dok1 A(439), A(443), A(446), and A(450) differed from wild-type Dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant Dok1 A(439), A(443), A(446), and A(450) also did not promote cell motility, whereas wild-type Dokl promoted cell motility, and Dok1 E-439, E-443, E-446, and E-450 further enhanced cell motility. These data indicate that IKKbeta phosphorylates Dok1 S439S443 and S446S450 after TNF-alpha, IL-1, or gamma-radiation and implicate the critical Dok1 serines in Dok1 effects after tyrosine kinase activation.
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