Our goal is to define the biochemical and medical importance of the posttranslational processing of CAAX proteins—including K-RAS and prelamin A—and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and other diseases.
The CAAX proteins undergo three posttranslational processing steps: prenylation, endoproteolysis, and methylation. These processing steps are mediated by five different enzymes (FTase, GGTase-I, RCE1, ZMPSTE24, ICMT) and render the carboxyl terminus of CAAX proteins hydrophobic stimulating interactions with membranes and effector proteins.
Mutations in the RAS proteins deregulate cell growth and are involved in the pathogenesis of cancer, such as lung-, colon, and pancreatic cancer and myeloid leukemia. Mutations in prelamin A causes Hutchinson-Gilford progeria syndrome – a pediatric syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., plasma membrane and nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif.
We use genetic strategies in mice to understand the importance of the CAAX protein processing enzymes for cellular transformation and the development of solid and hematopoietic tumors induced by mutations in RAS and RAF proteins and the neurofibromatosis 1 gene (NF1), and for the development of progeria induced by prelamin A accumulation. We also attempt to define the biochemical consequences of CAAX protein processing for protein–protein interactions, membrane association, and protein stability.
We use a range of molecular and cellular biology techniques in mouse and human cells and mouse models and genetic strategies to define mechanisms and treatment of human diseases using conditional and conventional knockout and transgenic mice.
Martin Bergö, PhD, Professor
Christin Karlsson, PhD
Jaroslaw Cisowski, PhD
Meng Liu, MD, PhD
Omar Khan, PhD student
Martin Dalin, PhD student
Mohamed Ibrahim, PhD student
Charles Liu, guest researcher
Frida Olofsson, Animal technician
Frida Larsson, Animal technician
Bjarni Thorisson, Animal technician
Murali Akula, Master student
Tony Zou, Master student
Volkan Sayin, PhD student, associate group member
Anna Staffas, PhD student, associate group member