The long range goals of this proposal are to define molecular mechanisms by which mechanical forcesexperienced by cells influence growth control pathways, and to determine where, when and how thesemechanisms are employed in vivo to modulate organ size. They build on the discovery in Drosophila of abiomechanical mechanism for modulating the Hippo pathway, which is a key regulator of growth and cell fate inall animals, including humans. This mechanism is triggered by cytoskeletal tension-dependent recruitment ofthe Ajuba family LIM protein (Jub) to α-catenin at adherens junctions. Jub then recruits and inhibits the keyHippo pathway kinase, Warts, which leads to increased activity of Yorkie, a transcription factor of the Hippopathway. Our studies will enhance understanding of how cells respond to their mechanical environment, howbiomechanical signaling is integrated with biochemical signaling, and how biomechanical signaling modulatesgrowth and cell fate decisions. The first aim proposes studies to identify components of this pathway inmammalian cells and to determine the contribution of this pathway to the regulation of Hippo signaling indifferent mechanical environments. We also propose to develop methods to visualize the activity of thispathway in live mice. The second aim proposes genetic and biochemical approaches to investigate themolecular mechanism by which forces are actually sensed and transmitted to the Ajuba and Warts familyproteins. The third aim investigates the relationship between the influence of cytoskeletal tension on Ajubafamily proteins, and its influence on β-catenin, through a combination of biochemical, imaging, and geneticapproaches, and will employ both Drosophila and cultured cell models. These studies investigate fundamental processes that cells use to respond to their mechanicalenvironment. The results of these studies will be relevant to understanding both normal development andphysiology, and to disease states associated with either insufficient or excess growth. As inappropriate growthduring development results in organs that are incorrectly sized or shaped, it can cause birth defects.Controlling organ growth is also important for understanding how stem cells can be used to repair or replacedamaged organs, which is a goal of regenerative medicine. Additionally, the inability to limit growth in matureorganisms results in cancer. Cancers in a wide variety of organs have been associated with inactivation ofHippo signaling, including liver, kidney, skin, brain, intestine, lung, ovary, breast, and prostate. Understandingthe regulation of Hippo signaling is thus relevant to a range of human health issues, including birth defects,cancer, and regenerative medicine.
|Effective start/end date||3/1/17 → 2/28/21|
- National Institutes of Health (NIH)