Induction of epithelial tubules by growth factor HGF depends on the STAT pathway

Hepatocyte growth factor (HGF) induces a three-phase response leading to the formation of branched tubular structures in epithelial cells 1 , 2 . The HGF receptor tyrosine kinase works through a Src homology (SH2) docking site that can activate several signalling pathways 3 . The first phase of the response (scattering), which results from cytoskeletal reorganization, loss of intercellular junctions and cell migration 4 , is dependent on phosphatidylinositol-3-OH kinase and Rac activation 5 , 6 . The second phase (growth) requires stimulation of the Ras–MAP kinase cascade 7 . Here we show that the third phase (tubulogenesis) is dependent on the STAT pathway. HGF stimulates recruitment of Stat-3 to the receptor, tyrosine phosphorylation, nuclear translocation and binding to the specific promoter element SIE. Electroporation of a tyrosine-phosphorylated peptide, which interferes with both the association of STAT to the receptor and STAT dimerization, inhibits tubule formation in vitro without affecting either HGF-induced ‘scattering’ or growth. The same result is obtained using a specific ‘decoy’ oligonucleotide that prevents STAT from binding to DNA and affecting the expression of genes involved in cell-cycle regulation (c- fos and waf-1 ). Activation of signal transducers that directly control transcription is therefore required for morphogenesis.