Research interests

- ADAM metalloprotease-disintegrins in human disease.
- Physiological and pathological regulation of ADAM genes and proteins.

Aims

ADAM metalloprotease-disintegrins mediate intercellular communication by proteolytically releasing active growth factors and other bioactive proteins from their membrane-bound precursors or removing receptors and adhesion proteins from the cell membrane (ectodomain shedding) and by cell adhesion. Our major aim is characterization and understanding of 1) Pathobiology and diagnostic/prognostic significance of aberrant ADAM regulation in human disease, especially in cardiovascular disease and cancer, and 2) Regulatory mechanisms controlling ADAM genes and proteins.

Our main focus is on the regulatory interactions between ADAMs and the cytosolic SH3-proteins and aberrant ADAM expression in cancer and atheroslerosis. The investigations are being done in close collaboration with other groups in Tampere and elsewhere.

We have identified SH3 proteins binding to the cytosolic domain of ADAMs in vitro and in cultured cells and further characterization is underway. ADAM15 gene contains alternatively used exons in the cytosolic-encoding region, potentially giving rise to several ADAM15 protein isoforms with different cytosolic tails in a tissue-spesific manner. Our recent findings show that the regulation of alternative ADAM15 exon use is altered in human breast cancer and malignant astrocytomas, leading to aberrant ADAM15 mRNA profiles. These non-random splice-variant patterns correlate with clinical traits of the tumors. Since the ADAM15 isoforms show differential interactions with cytosolic SH3 proteins, the aberrant splicing might contribute to misregulated function or location of ADAM15 protein. We also have recently shown that ADAM expressions are altered in atherosclerotic lesions.