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Receptor tyrosine kinase c-Kit signalling in hematopoietic progenitor cells
Umeå University, Faculty of Medicine, Medical Biosciences.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The receptor tyrosine kinase (RTK) c-Kit is expressed in hematopoietic stem and progenitor cells, mast cells and in several non-hematopoietic tissues. In the hematopoietic system c-Kit and its ligand Steel Factor (SF, aka Stem Cell Factor) are critical for proliferation, survival and differentiation. Mutations in either receptor or ligand lead to lethal anaemia, hematopoietic stem cell defects, mast cell deficiency and a series of non-hematological defects.

The aims of the studies included in this thesis are to describe the signalling pathways downstream c-Kit in hematopoietic stem/progenitor cells and to further analyse the role of c-Kit signalling in fundamental biological functions.

To study c-Kit signalling in the hematopoietic system we have employed hematopoietic stem cell-like cell lines which share many properties with primary hematopoietic stem cells in vitro and in vivo, including surface markers, multipotentiality, capacity for self-renewal and long term repopulation. In paper I we demonstrate that upon SF activation the RTK c-Kit is autophosphorylated and downstream signalling mediators are transiently activated. Surprisingly we find that the c-Kit mediated activation of the MAPK pathway is dependent on the activation of phosphoinositide 3-kinase (PI3K) in hematopoietic progenitor cells and that differentiation of these progenitors to mast cells results in a signalling switch where Raf activation changes from PI3K dependent to PI3K independent. We here establish that PI3K activity is required for viability and proliferation of hematopoietic progenitor cells. In paper II we studied the conventional protein kinase C (cPKC) involvement in c-Kit signalling. We observe that the cPKCs can phosphorylate c-Kit on serine 746 and that this phosphorylation negatively regulates the activation of the receptor. We demonstrate that inhibition of this negative phosphorylation results in dramatically increased protein kinase B (PKB) activation and as a consequence inhibition of cPKCs rescues cells from starvation induced apoptosis. Moreover we exhibit that the cPKCs are necessary for full activation of extracellular signal-regulated kinase (Erk) and that impaired PKC activity leads to hampered proliferation. In paper III we demonstrate that in addition to the cPKCs also the novel PKC is required for Erk activation and proliferation. Furthermore we present results indicating that PKC negatively regulates differentiation of bone marrow.

In conclusion, with the studies in this thesis we display details in the signalling pathways induced upon RTK c-Kit activation and we demonstrate that c-Kit has significant effects on hematopoietic cell-physiology.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap , 2006. , 60 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1058
Keyword [en]
RTK, c-Kit, MAPK, PI3K, PKC, hematopoietic cells, proliferation, differentiation, apoptosis
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-888ISBN: 91-7264-180-0 (print)OAI: oai:DiVA.org:umu-888DiVA: diva2:144893
Public defence
2006-10-27, Major Groove, 6L, umeå universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2006-10-10 Created: 2006-10-10 Last updated: 2009-10-02Bibliographically approved
List of papers
1. Activation of the MAP kinase pathway by c-Kit is PI-3 kinase dependent in hematopoietic progenitor/stem cell lines
Open this publication in new window or tab >>Activation of the MAP kinase pathway by c-Kit is PI-3 kinase dependent in hematopoietic progenitor/stem cell lines
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2004 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 104, no 1, 51-57 p.Article in journal (Refereed) Published
Abstract [en]

The Steel factor (SF) and its receptor c-Kit play a critical role for various cell types at different levels in the hematopoietic hierarchy. Whether similar or distinct signaling pathways are used upon c-Kit activation in different cell types within the hematopoietic hierarchy is not known. To study c-Kit signaling pathways in the hematopoietic system we have compared c-Kit downstream signaling events in SF-dependent hematopoietic stem cell (HSC)–like cell lines to those of mast cells. Both Erk and protein kinase B (PKB)/Akt are activated by ligand-induced activation of the c-Kit receptor in the HSC-like cell lines. Surprisingly, phosphoinositide-3 (PI-3) kinase inhibitors block not only PKB/Akt activation but also activation of Raf and Erk. SF-induced activation of Ras is not affected by inhibition of PI-3 kinase. In mast cells and other more committed hematopoietic precursors, the activation of Erk by SF is not PI-3 kinase dependent. Our results suggest that a molecular signaling switch occurs during differentiation in the hematopoietic system whereby immature hematopoietic progenitor/stem cells use a PI-3 kinase–sensitive pathway in the activation of both Erk and PKB/Akt, which is then switched upon differentiation to the more commonly described PI-3 kinase–independent mitogen-activated protein (MAP) kinase pathway.

Keyword
1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/*metabolism, Animals, Cell Line, Chromones/pharmacology, Enzyme Activation, Enzyme Inhibitors/pharmacology, Femur/cytology, Hematopoietic Stem Cells/cytology/*enzymology, MAP Kinase Signaling System/*physiology, Mice, Mice; Inbred C57BL, Mitogen-Activated Protein Kinases/metabolism, Morpholines/pharmacology, Phosphorylation, Protein-Serine-Threonine Kinases/metabolism, Proto-Oncogene Proteins/metabolism, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-kit/*metabolism, Proto-Oncogene Proteins c-raf/metabolism, Stem Cell Factor/metabolism, ras Proteins/metabolism
Identifiers
urn:nbn:se:umu:diva-15405 (URN)10.1182/blood-2003-07-2554 (DOI)14996702 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
2. Hematopoietic progenitor cells and mast cells utilize conventional PKC to suppress PKB/Akt activity in response to c-Kit stimulation
Open this publication in new window or tab >>Hematopoietic progenitor cells and mast cells utilize conventional PKC to suppress PKB/Akt activity in response to c-Kit stimulation
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-5389 (URN)
Available from: 2006-10-10 Created: 2006-10-10 Last updated: 2010-01-13Bibliographically approved
3. PKCdelta is required for proliferation and can negatively regulate differentiation in c-Kit expressing hematopoietic cells
Open this publication in new window or tab >>PKCdelta is required for proliferation and can negatively regulate differentiation in c-Kit expressing hematopoietic cells
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-5390 (URN)
Available from: 2006-10-10 Created: 2006-10-10 Last updated: 2010-01-13Bibliographically approved

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