Abstract
Adhesive interactions between cells and extracellular matrix
proteins play a vital role in biological processes such as cell
proliferation, differentiation and survival. Integrins comprise
a major family of cell surface receptors that mediate these interactions.
Integrin engagement triggers adhesion-dependent intracellular signalling
cascades that include the phosphorylation of tyrosines in intracellular
signalling proteins. Integrin-dependent signals act in concert
with signals from growth factors and other signalling receptors.
The objective of this thesis was to study how cell adhesion and growth
factors interact with intracellular components to regulate cell
behavior in normal and transformed cells.
One of the main proteins phosphorylated following integrin
ligation in several different cell types is the docking protein
p130Cas (Cas), which is tyrosine phosphorylated
after stimulation of cells with low concentrations of epidermal
growth factor (EGF). Tyrosine-phosphorylated Cas associates with
an adapter protein c-Crk, the main binding protein for Cas, suggesting
a novel role for EGF in Cas signalling. The interaction of cells
with a variety of agonists such as growth factors and integrin ligation
results in stimulation of mitogen-activated protein kinases (MAPKs),
which control the expression of genes important for many cell functions.
Expression of Cas and Crk induces activation of C-Jun N-terminal
kinases (JNKs), which are members of MAPK family. JNK activation
induced by integrin ligand binding is blocked by the expression
of a dominant-negative mutant of Cas or Crk demonstrating an important
role for the Cas-Crk complex in integrin-mediated JNK activation.
The proto-oncogene product p120Cbl (Cbl)
was identified as the main tyrosine-phosphorylated protein following
integrin ligation in hematopoietic cells of myeloid lineage. Tyrosine-phosphorylated
Cbl interacts with and activates other signalling proteins, such
as Src tyrosine kinase and phosphatidylinositol 3"-kinase
(PI 3-kinase), thereby mediating adhesion-dependent signals in hematopoietic
cells. Unlike the cellular Cbl, the transforming mutants of Cbl
were tyrosine-phosphorylated in an adhesion-independent manner
and interacted with and activated signalling molecules both in
suspended and in adherent cells. Further, the oncogenic forms of
Cbl induced anchorage-independent but serum-dependent proliferation
of cells. These results support the view that transformation by
Cbl results from constitutive activation of integrin-dependent
rather than growth factor-dependent signalling events.
| Identifer | oai:union.ndltd.org:oulo.fi/oai:oulu.fi:isbn951-42-5307-8 |
| Date | 23 June 1999 |
| Creators | Ojaniemi, M. (Marja) |
| Publisher | University of Oulu |
| Source Sets | University of Oulu |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:eu-repo/semantics/publishedVersion |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess, © University of Oulu, 1999 |
| Relation | info:eu-repo/semantics/altIdentifier/pissn/0355-3221, info:eu-repo/semantics/altIdentifier/eissn/1796-2234 |
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