Growth hormone receptor (GHR) is a cytokine receptor family member that responds to growth hormone (GH) by activation of the receptor-associated tyrosine kinase, JAK2. We previously showed that JAK2, in addition to being a signal transducer, dramatically increases the half-life of mature GHR, partly by preventing constitutive GHR downregulation. Herein we explored GHR and JAK2 determinants for both constitutive and GH-induced GHR downregulation, exploiting the previously characterized GHR- and JAK2-deficient 2A reconstitution system. We found that JAK2's ability to protect mature GHR from rapid degradation measured in the presence of the protein synthesis inhibitor, cycloheximide (CHX), depended on the presence of GHR's Box 1 element and the intact JAK2 FERM domain, but not the kinase-like or kinase domains of JAK2. Thus, GHR-JAK2 association, but not JAK2 kinase activity, is required for JAK2 to inhibit constitutive GHR downregulation and enhance GHR half-life. In cells that expressed JAK2, but not cells lacking JAK2, GH markedly enhanced GHR degradation. Like JAK2-induced protection from constitutive downregulation, GH-induced GHR downregulation required the GHR Box 1 element and an intact JAK2 FERM domain. However, a JAK2 mutant lacking the kinase-like and kinase domains did not mediate GH-induced GHR downregulation. Likewise, a kinase-deficient JAK2 was insufficient for this purpose, indicating that kinase activity is required. Both lactacystin (a proteasome inhibitor) and chloroquine (a lysosome inhibitor) blocked GH-induced GHR loss. Interestingly, GH-induced GHR ubiquitination, like downregulation, was prevented in cells expressing a kinase-deficient JAK2 protein. Further, a GHR mutant all of whose cytoplasmic tyrosine residues were changed to phenylalanines was resistant to GH-induced GHR ubiquitination and downregulation. Collectively, our data suggest that determinants required for JAK2 to protect mature GHR from constitutive degradation differ from those that drive GH-induced GHR downregulation. The latter requires GH-induced JAK2 activation and GHR tyrosine phosphorylation, and is correlated to GHR ubiquitination in our reconstitution system.