Cell surface levels of GHR are the primary determinant of GH responsiveness. This is modulated partly by endocytosis and lysosomal degradation. This downregulation is strongly inhibited by the association of JAK2 with the receptor, and by GH if JAK2 is prevented from signaling, but markedly enhanced by GH if JAK2 is kinase active. GH down-regulation also requires GHR tyrosine phosphorylation (Deng et al. 2007) and is believed to be mediated by GHR ubiquitination and proteasomal degradation.