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Stem Cell Factor Induced Signal Transduction
Uppsala University, Units outside the University, Ludwig Institute for Cancer Research.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Stem Cell Factor (SCF) can function as a survival factor, a mitogen or a chemoattractant depending on cell type. Binding of SCF to c-Kit induces dimerization and subsequent autophosphorylation of the receptor. This thesis describes the intracellular signal transduction elicited by c-Kit.

In the search for signal transduction molecules binding to activated c-Kit, we identified the adaptor proteins Grb2 and Grb7 as interacting partners. Grb2 could associate to Tyr-703 in the kinase insert as well as to Tyr-936 in the C-terminal tail of c-Kit. However, Grb7 could only bind to Tyr-936.

Tyr-568 in c-Kit is essential for SCF induced association and activation of Src family kinases (SFK). A mutated receptor that could not activate SFK (Y568F or Y568/570F) showed reduced Shc phosphorylation, Ras GTP loading, Erk activation and induction of c-fos. However, activation of SFK is not essential for the mitogenic response as measured by DNA synthesis.

Tyr-900 in c-Kit was identified as a SFK dependent phosphorylation site. The adaptor protein Crk and the p85 subunit of PI3’-kinase could associate with phosphorylated Tyr-900. In addition, we could demonstrate a constitutive complex between Crk and p85, suggesting indirect binding of Crk to Tyr-900 via p85. Mutation of Tyr-900 (Y900F) led to a reduced phosphorylation of Crk-II, loss of the second wave of Erk phosphorylation and a reduced mitogenic response. In addition the mutated receptor showed an increased ligand-induced degradation as compared to the wild-type receptor.

There exist two splice forms of c-Kit that differ in the presence or absence of four amino acids in the extracellular juxtamembrane region. These splice forms bind SCF with similar affinity but display striking differences in signaling characteristics, e.g. in phosphorylation kinetics, ligand-induced c-Kit degradation and activation of Erks. However, other pathways are activated similarly by both splice forms, such as the Ser/Thr kinase Akt which lies downstream of PI3’-kinase. In this study we show that differential phosphorylation of the various tyrosine residues occurs. Interestingly, Tyr-568 is more efficiently phosphorylated in the shorter form leading to stronger binding of SFK, whereas the PI3’-kinase binding site showed a similar degree of phosphorylation consistent with the data on Akt activation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2002. , p. 59
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1142
Keyword [en]
Oncology
Keyword [sv]
Onkologi
National Category
Cancer and Oncology
Research subject
Molecular Cellbiology
Identifiers
URN: urn:nbn:se:uu:diva-2003ISBN: 91-554-5291-4 (print)OAI: oai:DiVA.org:uu-2003DiVA, id: diva2:161616
Public defence
2002-05-17, B22/BMC, Uppsala, 09:15
Opponent
Available from: 2002-04-24 Created: 2002-04-24Bibliographically approved

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