FER Kinase Activation of Stat3 Is Determined by the N-terminal Sequence

Abstract p94fer and p51ferTare two tyrosine kinases that share identical SH2 and kinase domains but differ in their N-terminal regions. To further explore the cellular functions of these two highly related tyrosine kinases, their subcellular distribution profiles and in vivophosphorylation activity were followed using double immunofluorescence assay. When combined with immunoprecipitation analysis, this assay showed that p94fer can lead to the tyrosine phosphorylation and activation of Stat3 but not of Stat1 or Stat2. Native p94fer exerted this activity when residing in the cytoplasm. However, modified forms of p94fer, which are constitutively nuclear, could also lead to the phosphorylation of Stat3. Endogenous Stat3 and p94fer co-immunoprecipitated with each other, thus proving the interaction of these two proteinsin vivo. Unlike p94fer, p51ferT did not induce the phosphorylation of Stat3 but led to the phosphorylation of other nuclear proteins. Replacing the unique 43-amino acid-long N-terminal tail of p51ferT with a parallel segment from the N-terminal tail of p94fer did not change the subcellular localization of p51ferT but enabled it to activate Stat3. Thus the different N-terminal sequences of p94fer and p51ferT can affect their ability to induce phosphorylation of Stat3 and most probably direct their different cellular functions.