کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5527242 | 1401573 | 2017 | 10 صفحه PDF | دانلود رایگان |
- ITGB4 ligation in A431 cells regulates Src phosphorylation/activation.
- 12LOX enzymatic activity is increased by ITGB4-induced pSrc phosphorylation.
- Tyrosine residues 19 and 614 in 12LOX are pSrc targets post ITGB4 ligation.
- Phosphorylation state of 12LOX Y19 and Y614 influences cancer phenotypes.
12-Lipoxygenase (12-LOX) metabolizes arachidonic acid to 12(S)-hydroxyeicosatetraenoic acid, or 12(S)-HETE, a proinflammatory bioactive lipid implicated in tumor angiogenesis, growth, and metastasis. The mechanisms underlying 12-LOX-mediated signaling in cancer progression are still ill-defined. In the present study we demonstrate that 12-LOX phosphorylation and subsequent enzymatic activity occurs after integrin β4 stimulation and Src kinase recruitment to the integrin subunit. Inhibition of Src activity by PP2 or Src dominant-negative mutants reduced 12-LOX tyrosine phosphorylation and 12(S)-HETE production in response to integrin β4 stimulation in A431 cells. The pertinent Src-targeted residues for 12-LOX activity were mapped to Y19 and Y614, where 12-LOX mutants Y19F and Y614F showed 70% less enzymatic activity. Furthermore, we have shown that the 12-LOX activity modulated by these residues impacts migration. To our knowledge, this is the first report that c-Src kinase activity is required for β4-integrin-mediated phosphorylation of 12-LOX.
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Journal: Experimental Cell Research - Volume 351, Issue 1, 1 February 2017, Pages 1-10