Mechanism and Function of the Interactions of the Tumor Suppressor Merlin with Key Binding Partners in Neurofibromatosis II
Abstract
Patients with the inherited or sporadic mutations in the Neurofibromatosis Type II (NF2) gene develop a number of incurable neurological tumors, including schwannomas, meningiomas, and ependymomas, and they also can develop a malignant tumor in their lungs called mesothelioma. Further, young adults having inherited NF2 often have neurological or hearing deficits. The NF2 gene encodes for a protein termed merlin (for moesin-ezrinradixin-like protein), which functions as a protein that links key cell surface receptors called cadherins that direct cell-cell contacts to the actin cytoskeleton of the cell. Notably, loss-of-function merlin mutants found in NF2 disrupt cell-cell contacts and this provokes uncontrolled growth of these cells and, ultimately, the development of NF2-associated malignancies. Rationale and Objectives: The development of effective and safe therapeutics that can be used to combat the incurable malignancies that are a hallmark of NF2 requires a detailed understanding of the molecular basis of this disease. Loss-of-function mutations of merlin are the hallmark of NF2. For merlin to function, it must localize to the cell membrane, and it is thought that binding of merlin to a signaling lipid called PIP2 is important for this process. We will therefore determine the effects of PIP2 on the structure, localization, and function of merlin. Merlin also binds to a signaling protein called Lats1 that functions in a pathway that controls cell size, the Hippo (short for hippopotamus) pathway. Signaling by Lats1 keeps the Hippo pathway in an "off" state that restrains cell growth, and recent genetic and biochemical studies have shown that merlin and Lats1 bind to each other and that this interaction activates Lats1 to keep the Hippo pathway off. Thus, we will define (i) how merlin binds to F-actin, (ii) the crystal structures of the merlin/Lats1 and merlin/PIP2 complexes, and (iii) the roles of PIP2 and F-actin binding on the interaction of merlin with Lats1, and in controlling the Hippo pathway. Clinical Applicability of the Proposed Research: The proposed studies focus on defining the structure of merlin in complex with key partners and how merlin mutants that are found in NF2 affect these interactions. We submit that the proposed studies will eventually lay the groundwork for the development of small molecule screens that monitor the interaction of merlin recruitment of Lats1 and that this is facilitated by the interactions of merlin with actin cytoskeleton, and that the Lats1 interaction severs the merlin head-tail interaction, thereby increasing the binding for PIP2 that maintains merlin in an open state that is competent to activate Lats1. Contributions to Advancing the Field of NF Research: It has recently become clear, that the structure of merlin differs from the generally accepted model that is based on the structural and functional relationship of the ERM proteins and underscores the importance of structural studies of merlin in particular to understand its mechanism of activation. However, despite intensive efforts to obtain structural data on merlin only very limited data are available. The proposed studies will thus fill a void and determine the molecular details of several states of merlin with key binding partners. We submit that fully understanding the structure and function of merlin is necessary for the design and development of targeted therapeutics for treating NF2 patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510146
Entities
People
- Tina Izard
Organizations
- Scripps Research
- United States Army