P53 ASSOCIATES WITH TRK TYROSINE KINASE

The p53 tumor suppressor gene encodes a phosphoprotein which when over expressed can induce growth arrest at the G1 and G2/M phases of the ce ll cycle, promote differentiation and apoptosis. This paper demonstrat es that p53 can associate with trk tyrosine kinase. Expression of a mu rine temperature-sensitive (ts) p53 mutant in PC12 cells overexpressin g trk (a model system to analyse cellular differentiation and signal t ransduction induced by NGF) induces morphological changes in the absen ce of NGF stimulation at 32 degrees C but not at 37 degrees C. In cell s differentiated by p53, trk, but not EGFr, was hyperphosphorylated on tyrosine. Furthermore trk was not phosphorylated when expressed in Sa os-2 cells (human osteosarcoma cells that lack expression of both endo genous trk and p53) at either temperature. However, transfection of ts p53 into these cells induces trk phosphorylation at 32 degrees C in t he absence of NGF stimulation. Association of trk and p53 can be detec ted in NIH3T3 and PC12 cells co-expressing trk and the ts p53 mutant, in NIH3T3 and PC12 cells transfected with trk alone, and in untransfec ted PC12 cells, showing that overexpressed and/or endogenous trk assoc iates with endogenous, low levels of p53. These data suggest a novel f unction for p53 which involves the stimulation of signal transduction pathways (mediating morphological properties of cells), possibly throu gh association with and hyperphosphorylation of trk.