The presence of growth hormone receptor in the cell nucleus correlates with cell division, and targeting the GHR to the nucleus results in constitutive proliferation and transformation because of increased sensitivity to autocrine GH. Here we have sought additional mechanisms which might account for the enhanced proliferation seen with nuclear GHR, commencing with a yeast 2-hybrid screen for interactors with the extracellular domain of the GHR (GHBP). We find that the GHBP is a transcriptional activator in yeast and mammalian cells, and this activity resides in the lower cytokine receptor module. Activity is dependent on S226, the conserved serine of the cytokine receptor consensus WSXWS box. By using parallel GHBP affinity columns and MS/MS of tryptic digests of proteins bound to WT GHBP and S226A columns, we identified proteins which bind to the transcriptionally active GHBP. These include a nucleoporin and two transcriptional regulators, notably the Coactivator Activator (CoAA), which is also an RNA binding splicing protein. Binding of CoAA to the GHBP was confirmed by GST pulldown and co-immunoprecipitation, and shown to be GH-dependent in pro-B Ba/F3 cells. Importantly, stable expression of CoAA in Ba/F3 cells resulted in an increased maximum proliferation in response to GH, but not IL-3. Since CoAA overexpression has been identified in many cancers and its stable expression promotes cell proliferation and cell transformation in NIH-3T3 cells, we suggest CoAA contributes to the proliferative actions of nuclear GHR by the hormone-dependent recruitment of this powerful coactivator to the GHR.