Research / Clinical Summary

Gernot Walter, PhD Professor Emeritus, Pathology Cancer Biology Program Contact by Email

The main goal of Dr. Walter's laboratory is to demonstrate that a specific form of protein phosphatase 2A (PP2A) plays a role as tumor suppressor in humans. The PP2A holoenzyme is a heterotrimer composed of a catalytic C subunit (Cα or Cβ), a scaffolding A subunit (Aα or Aβ), and a regulatory B subunit (B, B' or B'). The genes encoding Aα and Aβ were found to be mutated in a significant number of human carcinomas.

Importantly, they found that all cancer-associated Aα mutations encode proteins that are defective in binding B, B', B'' and/or C subunits. One of the most specific Aα mutations is the point mutation E64D that was detected in lung cancer. The E64D protein is incapable of binding B' subunits and forming B'-containing holoenzymes, while binding of B, B'', and C subunits is normal. They hypothesize that one or several B'-containing holoenzymes act as tumor suppressors. To obtain direct evidence for this hypothesis, his group recently generated knock-in mice expressing the E64D mutation. If these mice develop lung cancer, they conclude that PP2A is a tumor suppressor in mice and probably humans. They also generated a conditional Aα subunit knock-out mouse. Both mice together will allow us to study the role of PP2A in all human cancers in which Aα subunit mutations have been discovered, including breast, colon and lung carcinomas, as well as melanomas.

Another interest of this laboratory is the role of PP2A in DNA replication and checkpoint control. Using a cell-free, soluble DNA replication system derived from Xenopus eggs, they demonstrated that removal of PP2A from replication extracts, or inhibition of PP2A by okadaic acid, inhibits initiation of DNA replication by preventing loading of the initiation factor Cdc45 onto pre-replication complexes. They also showed that PP2A antagonizes the checkpoint kinases ATM and ATR in a DNA damage checkpoint. They are interested in finding out whether PP2A has similar functions in mammalian cells and what its substrates are in checkpoint control.

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