Abstract
The ubiquitin-proteasome system is required in growth hormone receptor (GHR) endocytosis. For cytokine receptors, which lack intrinsic tyrosine kinase activity, signal transduction is initiated by the activation of a member of the Janus kinase (JAK) family. Previously, we have shown that GHR and JAK2 tyrosine (de) phosphorylation are regulated via the ubiquitin system. In this study, we examined the role of JAK2-mediated signal transduction in GHR internalization and down-regulation. Mutation of the attachment site for JAK2, box-1, in the GHR cytoplasmic tail resulted in the complete absence of GHR and JAK2 phosphorylation. This modification did not alter the rate and extent of receptor-bound growth hormone internalization as compared with a functional GHR, nor did it change its turnover and transport to the plasma membrane. In addition, the receptor was still normally ubiquitinated and remained dependent on both an intact ubiquitin system and proteasomal action for its internalization. Thus, GHR ubiquitination, endocytosis, and degradation occur independently of GHR signal transduction via JAK2. We conclude that whereas endocytosis and degradation require the ubiquitin system, they are independent of GHR signal transduction.
Highlights
GH1 regulates important physiological processes such as growth, metabolism, and cellular differentiation
JAK2 Binding and Activation Is Absent in a Box-1-mutated growth hormone receptor (GHR)—To determine whether activation of the GHR and downstream signaling components are involved in GH-dependent endocytosis, the four proline residues between amino acids 280 –287 in box-1 of the cytosolic tail of the GHR were mutated to alanines (GHR4P-A)
JAK2 did not become tyrosine phosphorylated upon GH addition in cells expressing the GHR4P-A (Fig. 1B)
Summary
GH1 regulates important physiological processes such as growth, metabolism, and cellular differentiation. In the EGF receptor, mutation of its intrinsic tyrosine kinase activity abolished both signaling transduction and ligand-induced down-regulation/endocytosis [26, 27], whereas other receptors (e.g. transferrin) were internalized through coated pits without any known kinase requirement [23].
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