Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.
Post-translational modifications of the env-sea tyrosine kinase and their role in transformation.
Diss Abstr Int [B]; 54(5):2356 1993. Unique Identifier : AIDSLINE ICDB/94698736 Crowe AJ; State Univ. of New York at Stony Brook
Abstract:
Analysis of the oncogenic counterparts of receptor tyrosine kinases has enabled researchers to study how oncoproteins transform cells, as well as to gain insights into the signal transduction pathway initiated by receptors in normal cells. V-sea is a member of the growth factor receptor family of tyrosine kinases. Our analysis of the intracellular processing of the sea oncoprotein indicates that v-sea, like other retroviral env proteins and growth factor receptors such as the insulin receptor and the hepatocyte growth factor receptor (c-met), encodes a precursor protein which undergoes proteolytic processing and terminal glycosylation in the Golgi to yield the complex carbohydrate forms which are then transported to the cell surface. Both mutagenesis and glycosylation inhibitors were employed to determine the role of post translational modifications of v-sea in transformation. First, mutagenesis of the invariant lysine residue in the ATP-binding domain confirmed that tyrosine kinase activity is necessary for v-sea-mediated transformation. Secondly, replacement of the env domain of v-sea with a myristylation signal indicated that the envelope domain itself was not essential for transformation by v-sea, but may be necessary to target a transformation-competent form of the tyrosine kinase to the membrane. In addition, characterization of two cleavage mutants in v-sea has determined that proteolytic processing to the mature gp70env-sea form is not essential for transport, tyrosine kinase activity, or transformation by v-sea. These results suggest that, in the absence of gp70env-sea a terminally glycosylated uncleaved precursor is transported to the cell surface and can functionally substitute for gp70env-sea as a transforming protein. Inhibiting the formation of these cell surface forms, either by shifting to the restrictive temperature for the ts-sea oncogene, or by treatment with the glycosylation inhibitor castanospermine, causes v-sea transformed cells to revert to a normal phenotype. Together, our data support a model in which both tyrosine kinase activity and correct cell surface localization are necessary for transformation by v-sea, while proteolytic processing and terminal glycosylation are not. However, these latter two processes may serve to stabilize the correct conformation of the v-sea protein, thus ensuring its efficient transport to and expression at the cell surface. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD93-28178)
Keywords: Cell Transformation, Neoplastic/GENETICS Gene Products, env/*METABOLISM Glycosylation Hepatocyte Growth Factor/METABOLISM Mutagenesis Oncogene Proteins, Viral/*METABOLISM *Protein Processing, Post-Translational Protein-Tyrosine Kinase/METABOLISM Proto-Oncogene Proteins/GENETICS/METABOLISM Receptor Protein-Tyrosine Kinase/GENETICS/METABOLISM THESIS 940630
M9460920
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Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.
