Thelong-termgoalofourresearchistounderstandthemolecularmechanismsthatcontroleukaryoticsignaling pathways. The objective of this application is to elucidate the principles that regulate the core kinases in the Hippopathway.TheHippopathwaycontrolsorgansizeduringdevelopment,tumorigenesis,andmaintainsthe stem-cell niche through the coordinated activity of a kinase cassette that includes two kinases, Mst1/2 and Lats1/2, and two accessory proteins, Mob1 and hSalvador.
In Aim 1, we will establish a molecular basis for understandingcomplexformationbetweenSARAHdomainproteins(hSalvador,Mst1/2,andRassF5)toinform onhowtheseproteinsregulatepathwayactivity.
In Aim2, ourinvestigationswillfurtherunderstandingofMst1/2 activationandprovideamechanisticlinkbetweenupstreampathwaycomponentsandkinaseactivation.
In Aim 3 wewillelucidatethemolecularmechanismsgoverningtheactivityofLats1andMst2activity.Outcomesfrom the proposed work will fundamentally alter our picture of Hippo signaling in normal and disease states and stimulatenewdirectionsofcellularandtherapeuticinvestigation.
Theactivity of the Hippopathway regulates cell proliferation, stem cell maintenance, tumorigenesis. This work will determine the molecular mechanisms regulating kinase activity in the pathway. Insight gained from the proposed work will guide future efforts developing therapeutics that target the pathway with anti-cancer or tissue/organrepairandregenerationproperties.
