Cell cycle-dependent nuclear accumulation of the p94(fer) tyrosine kinase is regulated by its NH₂ terminus and is affected by kinase domain integrity and ATP binding

p94(fer) and p51(ferT) are two tyrosine kinases that are encoded by differentially spliced transcripts of the FER locus in the mouse. The two tyrosine kinases share identical SH2 and kinase domains but differ in their NH₂-terminal amino acid sequence. Unlike p94(fer), the presence of which has been demonstrated in most mammalian cell lines analyzed, the expression of p51(ferT) is restricted to meiotic cells. Here, we show that the two related tyrosine kinases also differ in their subcellular localization profiles. Although p51(ferT) accumulates constitutively in the cell nucleus, p94(fer) is cytoplasmic in quiescent cells and enters the nucleus concomitantly with the onset of S phase. The nuclear translocation of the FER proteins is driven by a nuclear localization signal (NLS), which is located within the kinase domain of these enzymes. The functioning of that NLS depends on the integrity of the kinase domain but was not affected by inactivation of the kinase activity. The NH₂ terminus of p94(fer) dictated the cell cycle-dependent functioning of the NLS of FER kinase. This process was governed by coiled- coil forming sequences that are present in the NH₂ terminus of the kinase. The regulatory effect of the p94(fer) NH₂-terminal sequences was not affected by kinase activity but was perturbed by mutations in the kinase domain ATP binding site. Ectopic expression of the constitutively nuclear p51(ferT) in CHO cells interfered with S-phase progression in these cells. This was not seen in p94(fer)-overexpressing cells. The FER tyrosine kinases seem, thus, to be regulated by novel mechanisms that direct their different subcellular distribution profiles and may, consequently, control their cellular functioning.