Research
We are investigating a signaling pathway that regulates cell proliferation
and cell death. This pathway was originally identified in Drosophila melanogaster. It comprises serine/threonine kinases, an adaptor protein, a kinase activator,
cytoskeleton-related proteins, and a transcription co-activator. Recent
studies have revealed a cell adhesion molecule and a putative Ras effector
as additional components of the pathway. Importantly, all these components
have mammalian homologues, indicating that this pathway is conserved in
mammals.
In fly, the pathway restricts cell growth and promotes cell death to control
organ size. The mutations of the components cause disruption in cell adhesions
and abnormal cell proliferation. We initially encountered with this pathway
in the course of the study on the molecular organization of cell junctions.
We found one molecule as a binding partner for a cell adhesion molecule-associated
protein. The molecule turned out to be related to a component of this pathway.
Thereby, we consider that this pathway is closely related to cell adhesion.
Normal epithelial cells die when they are detached from the cell matrix
and lose cell adhesion. In contrast, cancer cells, especially when they
are metastatic, survive in an anchorage-independent manner. We speculate
that the disorders of this pathway are implicated in cancer metastasis
and that the re-activation of this pathway is useful to block metastasis.
Data from our group and others also suggest that this pathway plays a role
in the cell death triggered by cytokines and irradiation. Thus, we further
speculate that this pathway is also involved in the cell death observed
in various pathological conditions (inflammation, ischemia, trauma, ageing).
In this context, the suppression of this pathway may be therapeutically
meaningful.
Some components are enriched in neurons in brain. In the first place, we
suspect that they are important in neuronal degenerative diseases. However,
the pathway may have an additional function in brain. The pathway is suggested
to regulate dendritic morphogenesis in fly. If this pathway is truly related
to cell adhesion, the pathway may be important to establish and maintain
neural circuit.