Fox Chase Cancer Center
PHILADELPHIA (March 11, 2019) — Adhesion of lymphocytes to their cellular targets is critical to adaptive immunity, the body’s ability to assign specific antibodies to pathogens. This process is controlled by a group of cell surface receptors called integrins through a cascade of molecular events known as inside-out signaling. This pathway is regulated by a small GTPase closely related to the RAS oncogene called RAP1.
Jinhua Wu, PhD, associate professor in the Molecular Therapeutics Program at Fox Chase Cancer Center, has found that the RAP1 function can be suppressed if its effector protein (RIAM) adopts an autoinhibitory configuration, and this suppression of RAP1 function is released once RIAM is phosphorylated. This result reveals the first example of a novel regulatory mechanism by which an effector protein is autoinhibited, thus offering a new strategy for the identification of novel targets to better treat autoimmune diseases associated with RAP1 and integrin.
Wu’s lab focuses on understanding the structural basis of intermolecular complexes and intramolecular rearrangements that control integrin-mediated cell adhesion and motility. Their aim is to enable the development of next-generation inhibitors by mapping the structural details of each signaling event involved in this pathway.
The paper, entitled, “Molecular basis for autoinhibition of RIAM regulated by FAK in integrin activation,” appears in Proceedings of the National Academy of Sciences.
This work was supported by grants GM119560 and CA163489 from the National Institutes of Health, 4100068716 from the Pennsylvania Department of Health, RSG-15-167-01-DMC from the American Cancer Society, and Pilot Project Award 5P30CA006927-51 made possible with a portion of the Cancer Center Support Grant.
About Fox Chase Cancer Center
The Hospital of Fox Chase Cancer Center and its affiliates (collectively “Fox Chase Cancer Center”), a member of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship and community outreach. For more information, call 1-888-FOX CHASE or (1-888-369-2427).