MAPPING OF A CYTOPLASMIC DOMAIN OF THE HUMAN GROWTH-HORMONE RECEPTOR THAT REGULATES RATES OF INACTIVATION OF JAK2 AND STAT PROTEINS

It has been previously demonstrated that growth hormone (GH)-stimulate d tyrosine phosphorylation of Jak2 and Stat5a and Stat5b occurs in FDP -C1 cells expressing either the entire GH receptor or truncations of t he cytoplasmic domain expressing only the membrane-proximal 80 amino a cids, However, other receptor domains that might modulate rates of GH activation and inactivation of this cascade have not been examined, He re we have defined a region in the human GH receptor between amino aci ds 520 and 540 in the cytoplasmic domain that is required for attenuat ion of GH-activated Jak/Stat signaling, Immunoprecipitations with anti bodies to Jak2 indicate that the protein tyrosine phosphatase SHP-1 is associated with this kinase in cells exposed to GH. To address the po ssibility that SHP-1 could function as a negative regulator of GH sign aling, liver extracts from motheaten mice deficient in SHP-1 or unaffe cted littermates were analyzed for activation of Stats and Jak2, Extra cts from motheaten mice displayed prolonged activation of the Stat pro teins as measured by their ability to interact with DNA and prolonged tyrosine phosphorylation of Jak2. These results delineate a novel doma in in the GH receptor that regulates the inactivation of the Jak/Stat pathway and appears to be modulated by SHP-1.