Change search
ReferencesLink to record
Permanent link

Direct link
PKCdelta is required for proliferation and can negatively regulate differentiation in c-Kit expressing hematopoietic cells
Umeå University, Faculty of Medicine, Medical Biosciences.
Manuscript (Other academic)
URN: urn:nbn:se:umu:diva-5390OAI: diva2:144892
Available from: 2006-10-10 Created: 2006-10-10 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Receptor tyrosine kinase c-Kit signalling in hematopoietic progenitor cells
Open this publication in new window or tab >>Receptor tyrosine kinase c-Kit signalling in hematopoietic progenitor cells
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.
Umeå University medical dissertations, ISSN 0346-6612 ; 1058
RTK, c-Kit, MAPK, PI3K, PKC, hematopoietic cells, proliferation, differentiation, apoptosis
National Category
Cell and Molecular Biology
urn:nbn:se:umu:diva-888 (URN)91-7264-180-0 (ISBN)
Public defence
2006-10-27, Major Groove, 6L, umeå universitet, Umeå, 13:00 (English)
Available from: 2006-10-10 Created: 2006-10-10 Last updated: 2009-10-02Bibliographically approved

Open Access in DiVA

No full text

By organisation
Medical Biosciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 27 hits
ReferencesLink to record
Permanent link

Direct link