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Investigation of receptor association and tyrosine phosphorylation of S6 kinases

Rebholz, Heike; (2004) Investigation of receptor association and tyrosine phosphorylation of S6 kinases. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

S6 kinase, a member of the AGC family of kinases, is activated by an array of mitogenic stimuli and is a key player in the regulation of cell growth and proliferation. The activation process involves a complex sequential series of ten or more serine and threonine phosphorylations. In this thesis it was investigated if S6K activation would involve translocation to the plasma membrane and if tyrosine phosphorylation would occur as was previously shown for some other AGC kinases. It is demonstrated for the first time that S6 kinase is associated with receptor protein tyrosine kinases (RTKs) upon growth factor stimulation. The binding occurs via the kinase or kinase extension domain of S6K as shown by the use of truncation mutants in co-immunoprecipitation studies. Furthermore, both isoforms of S6 kinase were shown to be phosphorylated on tyrosine in a RTK- and Src-dependent manner. Using mass spectrometry and truncation mutants, two phosphorylation sites were mapped: one is located in the activation loop and the second one in the N-terminus of the kinase. Inhibitor studies reveal that phosphorylation occurs independently of PI3 Kinase and mTor but is inhibited by Src family kinase inhibitors. It has already been established that expression of Src kinase leads to an activated S6K. However, as shown in this study, this effect is not mediated through tyrosine phosphorylation. Subcellular localisation and S6K stability are also not altered in a Src-dependent manner. Taken together, the presented work shows for the first time an additional mechanism of S6 kinase regulation via association with receptor tyrosine kinases and tyrosine phosphorylation. The phosphotyrosine site/s possibly create/s recognition sites for SH2 domain containing proteins and therefore may be important for recruiting S6K into a multienzyme complex with other signalling molecules at the plasma membrane.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigation of receptor association and tyrosine phosphorylation of S6 kinases
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Tyrosine phosphorylation
URI: https://discovery.ucl.ac.uk/id/eprint/10102714
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