HER4-MEDIATED BIOLOGICAL AND BIOCHEMICAL-PROPERTIES IN NIH 3T3 CELLS - EVIDENCE FOR HER1-HER4 HETERODIMERS

The EGF receptor family of tyrosine kinase growth factor receptors is expressed in a variety of cell types and has been implicated in the pr ogression of certain human adenocarcinomas. The most recent addition t o this family of receptors, HER4, was expressed in NIH 3T3 cells to de termine its biological and biochemical characteristics. Cells expressi ng HER4 were responsive to heregulin beta 2 as demonstrated by an incr ease in HERA tyrosine phosphorylation and ability to form foci on a ce ll monolayer. HER4 exhibited in vitro kinase activity and was able to phosphorylate the regulatory subunit of phosphatidylinositol 3-kinase and SHC. Peptide competition studies identified tyrosine 1056 of HER4 as the phosphatidylinositol 3-kinase binding site and tyrosines 1188 a nd 1242 as two potential SHC binding sites. Interestingly, transfectio n of HER4 into NIH 3T3 cells conferred responsiveness to EGF with resp ect to colony formation in soft agar. It was also found that in respon se to heregulin beta 2, endogenous murine HER1 or transfected human HE R1 became phosphorylated when HER4 was present. This demonstrates that HER1 and HER4 can exist in a heterodimer complex and likely activate each other by transphosphorylation.