Research Scientist Saara Tuomi from VTT and the University of Turku, has
presented her doctoral dissertation on 12 November.
Integrin transmembrane receptor functions are regulated by adaptor molecules
binding to their α and β subunit intracellular domains, or tails, thus
affecting integrin traffic and adhesion during e.g. cell motility.
Interestingly, many cellular proteins function in both cell motility and cell
division, thus raising the possibility that integrins might be involved in
regulating the cell cycle. A thorough understanding of cell division is
essential in cell biology and in human malignancies. It is well established
that failures to complete cell cycle can give rise to genetically unstable
cells with tumorigenic properties. Transformed cells promote the disruption of
intercellular adhesions such as tight junctions, and this correlates with the
onset of cell motility, invasion and unfavorable prognosis in cancer.
In
this study, we analyzed integrin regulation, mediated by adaptor binding to
the α subunit tail, during cell motility and cell division. We revealed a
novel molecular mechanism by which Rab21, through association with the
integrin α subunits, drives integrin endosomal traffic during mitotic phases.
In addition, we found indications for this finding in vivo, as RAB21 gene
deletions were mapped in ovarian and prostate cancer samples. Importantly, the
multinucleated phenotype of cultured ovarian cancer cells could be reverted by
Rab21 overexpression. In this thesis work, we also show how the tight junction
protein ZO-1 unexpectedly interacts with the α5 integrin cytoplasmic domain in
the lamellipodia to promote cell motility and at the cleavage furrow to
support separation of the daughter cells. The α5-ZO-1 complex formation was
dependent on PKCε which regulates ZO-1 phosphorylation and its subcellular
localization. In addition, by an in situ detection method, we showed that a
subset of metastatic human lung cancers expressed the α5β1-ZO-1 complex.
Taken
together, we were able to identify new molecular pathways that regulate
integrin functions in an α tail-mediated fashion. These findings firmly
suggest that genetic alterations in integrin traffic may lead to progression
of tumorigenesis as a result of failed cell division. Also, the interplay of
integrins and ZO-1 in forming spatially regulated adhesive structures broadens
our view of crosstalk between pathways and distinct adhesive structures that
can be involved in cancer cell biology.
Dissertation
