Proposing and Proving the concept of adapter molecules in the signal transduction
Dr. Anthony J. Pawson discovered that the bonding of a phosphorylated receptors with adapter proteins which carry a module he termed the "SH2 domain" induces cascades of intracellular signaling resulting in cell transformation. At this time, he worked hard to ensure that this concept became widely known, thereby making a vital contribution to the elucidation of the major molecular infrastructure that controls cell proliferation and differentiation.
The human body consists of about 60 trillion cells, and its life is maintained by the organic activity of cells based on the correct transduction of signals. Within a single cell, furthermore, the activation of various functions has various effects on the human body that are dependent on the correct transfer of signals from other cells arriving at the cell surface. Cancer, diabetes, autoimmune system disorders, and other diseases are all caused by malfunction of the intracellular signal transduction. Through his work from the mid 1980s to the early 1990s, Dr. Pawson made new discoveries about the mechanism of signal transduction within cells and went on to develop a new concept of intracellular signal transduction. His research has had a tremendous influence on virtually all fields of biomedical research, including developmental biology, neurobiology, endocrinology, immunology, hematology, and oncology. It has also been of extensive assistance in clarifying the mechanisms that cause cancer, diabetes, and other diseases.
[Intracellular signal transduction]
When hormones and other messenger molecules carrying information between cells bond with a receptor in the cell on the receiving side, the information is transferred to cascades within the cell by the interaction of multiple molecules triggered by this bonding (this is what is meant by signal transduction). The signal transduction results in processes such as cell differentiation and propagation, immunoreactions, and protein synthesis and secretion outside the cell. These cell reactions maintain life. Up until the 1980s, it was thought that cell interiors were filled with a "soup" of cytoplasm in which proteins and subcellular organelles (such as the nucleus and mitochondria) floated. This assumption made it difficult to explain how messenger molecules managed to unfailingly relay signals to the furthest recesses of the cells in spite of the lack of structures to transfer the message. One of the greater understanding we have today can be traced back to the discovery that a receptor tyrosine kinase, which catalyzes the phosphorylation of tyrosine (a type of amino acid), bonds with certain proteins within cytoplasm.
[Achievements of Dr. Pawson]
In the 1980s, a group headed by Dr. Pawson found that the bonding of a tryrosine-phosphorylated receptor with adapter proteins which have a module (base unit) he named the "SH2 domain" subsequently induces cascades of intracellular signaling resulting in cell transformation. Up until this discovery, it was thought that phosphorylation led to successive changes in the molecular structure and, in turn, signal transduction within the cell. In reality, however, there is absolutely no change in the chemical structure of the receptor; the group instead determined that the receptor and adapter are joined together by the mutual attraction of the positive charge on the SH2 domain and the negative charge of the phosphate group added to the tyrosine residue. Furthermore, the group proposed the concept of network formation through linkage of a plural number of modules of the adapters, and consequently created a new paradigm for signal transduction systems.
[Effects of signal transduction]
While many diseases are caused by malfunction of intracellular signal transduction, the most important is cancer. Cancer is characterized by uncontrolled cell division and its spread to other cells. For example, when mutations occur in genes involved in cell division, the abnormal proteins act as if they have been ordered to propagate cells although no such order was given, and continue to multiply without limit. Diabetes, in contrast, is caused by excessively faint intracellular signal transduction. More specifically, diabetes is caused if the receptor is unable to relay the message of insulin sent from the pancreas to molecules within the cell. Accordingly, it is anticipated that the elucidation of intracellular signal transduction will contribute to future treatment of cancer and autoimmune system diseases.
For more details, see the Achievements.
