Posttranslational modifications in the regulation of Growth Hormone Receptor and Jak2

Abstract

Growth hormone (GH), secreted by pituitary gland, regulates many important processes like growth, carbohydrate and lipid metabolism and immune responses. Growth hormone acts via growth hormone receptor (GHR) that is localised at the plasma membrane of every cell in the body. Binding of GH to GHR initiates a signalling cascade via STAT5/MAPK that leads to transcription of target genes. GHR needs Jak2 binding in order to perform a signalling. Deregulation of GHR signalling often leads to malignant transformation resulting in cancer. Additionally, many cancer and AIDS patients suffer from muscle wasting condition called cachexia due insufficient amount of GHR at the plasma membrane of their cells. This shows that availability of the receptor for GH signalling is an important issue. GHR is internalised in the process called endocytosis and degraded in the lysosome. In the thesis we optimised blue native electrophoresis method to analyse GHR complexes at early stages of receptor internalisation. Our results contribute to the understanding of the mechanism of GHR endocytosis and in the future may help to design new treatments for patients. Additionally, constitutive activity of Jak2 leads to myeloproliferative diseases. It has been proposed that the nuclear fraction of constitutively active Jak2 is especially malignant. In the thesis we identified a new posttranslational modification of Jak2 called sumoylation. We show that high molecular weight sumoylation regulates Jak2 shuttling between nucleus and cytoplasm. We provide evidence that sumoylation of Jak2 may be a previously unknown mechanism regulating availability of the kinase to cytokine signalling. Interfering with kinase sumoylation provides new therapeutic strategies for patients suffering from Jak2 related malignancies.