Focal adhesion kinase activated by β4 integrin ligation to mCLCA1 mediates early metastatic growth

Mossaad Abdel-Ghany, Hung Chi Cheng, Randolph C. Elble, Bendicht U. Pauli

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98 Citations (Scopus)


Early metastatic growth occurs at sites of vascular arrest of blood-borne cancer cells and is entirely intravascular. Here we show that lung colonization by B16-F10 cells is licensed by β4 integrin adhesion to the mouse lung endothelial Ca2+-activated chloride channel protein mCLCA1. In a manner independent of Met, β4 integrin-mCLCA1-ligation leads to complexing with and activation of focal adhesion kinase (FAK) and downstream signaling to extracellular signal-regulated kinase (ERK). FAK/ERK signaling is Src-dependent and is interrupted by adhesion blocking antibodies and by dominant-negative (dn)-FAK mutants. Levels of ERK activation in B16-F10 cells transfected with wild-type or mutant FAK are closely associated with rates of proliferation and bromodeoxyuridine (BrdUrd) incorporation of tumor cells grown in mCLCA1-coated dishes, the ability to form tumor cell colonies on CLCA-expressing endothelial cell monolayers, and the extent of pulmonary metastatic growth. Parallel with the transfection rates, B16-F10 cells transfected with dn-FAK mutants and injected intravenously into syngeneic mice generate approximately half the number and size of lung colonies that vector-transfected B16-F10 cells produce. For the first time, β4 integrin ligation to its novel CLCA-adhesion partner is shown to be associated with FAK complexing, activation, and signaling to promote early, intravascular, metastatic growth.

Original languageEnglish
Pages (from-to)34391-34400
Number of pages10
JournalJournal of Biological Chemistry
Issue number37
Publication statusPublished - 2002 Sept 13

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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