Not listed UNDERSTANDING THE FUNCTION OF MERLIN AND KIBRA IN PROMOTING HIPPO PATHWAY ACTIVATION - ABSTRACT THE HIPPO SIGNALING PATHWAY IS HIGHLY CONSERVED AND COORDINATES TISSUE GROWTH WITH MORPHOGENESIS IN ANIMAL DEVELOPMENT. HIPPO SIGNALING ALSO HAS A COMPLEX RELATIONSHIP WITH APICAL-BASAL POLARITY IN EPITHELIAL CELLS - DISRUPTIONS IN HIPPO SIGNALING RESULT IN A LARGER APICAL DOMAIN AND DISRUPTIONS OF APICAL POLARITY AFFECT HIPPO SIGNALING. IN POLARIZED EPITHELIA CELLS, MANY HIPPO PATHWAY COMPONENTS - CRUMBS, EXPANDED, KIBRA, MERLIN AND WARTS - ARE APICALLY LOCALIZED. HOW UPSTREAM PATHWAY COMPONENTS ARE ACTIVATED AND INTERACT WITH POLARITY DETERMINANTS IS NOT WELL UNDERSTOOD. I PROPOSE TO RIGOROUSLY STUDY HOW MERLIN AND KIBRA INTERACT TO REGULATE THE HIPPO PATHWAY, AND HOW THIS INTERACTION IS CONNECTED TO APICAL POLARITY. WORK FROM OUR LAB HAS SHOWN THAT MERLIN AND KIBRA WORK TOGETHER TO PROMOTE HIPPO SIGNALING, WHILE THE PAN LAB HAS PROPOSED THAT MERLIN AND KIBRA ACT INDEPENDENTLY TO ACTIVATE THE HIPPO PATHWAY. APKC, A MAJOR REGULATOR OF APICAL POLARITY, INHIBITS KIBRA'S ABILITY TO ACT IN THE HIPPO PATHWAY AND INFLUENCES KIBRA AND MERLIN'S SUBCELLULAR LOCALIZATION. TOGETHER THESE STUDIES SUGGEST FUNCTIONAL INTERACTIONS BETWEEN APICAL POLARITY PROTEINS, MERLIN, AND KIBRA ARE IMPORTANT FOR REGULATION OF HIPPO-MEDIATED GROWTH CONTROL. IN THIS PROPOSAL, I PLAN TO ASK: 1) DO MERLIN AND KIBRA FUNCTION BOTH SEPARATELY AND TOGETHER IN THE HIPPO PATHWAY? AND 2) WHAT IS THE RELATIONSHIP BETWEEN APICAL POLARITY IN REGULATING KIBRA AND MERLIN LOCALIZATION AND HIPPO PATHWAY ACTIVITY? THESE STUDIES WILL BE CONDUCTED IN DROSOPHILA EPITHELIAL TISSUES SINCE DROSOPHILA HAVE SOPHISTICATED GENETIC, MOLECULAR, AND CELLULAR METHODS, AND HAVE BEEN WIDELY USED TO STUDY THE HIPPO PATHWAY AND APICAL POLARITY. FINDINGS FROM THIS WORK WILL PROVIDE NOVEL MOLECULAR INSIGHTS INTO HOW MERLIN AND KIBRA FUNCTION AS TUMOR SUPPRESSOR PROTEINS THROUGH REGULATION OF THE HIPPO PATHWAY. $50.1k 6/8/26 Not listed UNDERSTANDING THE FUNCTION OF MERLIN AND KIBRA IN PROMOTING HIPPO PATHWAY ACTIVATION - ABSTRACT THE HIPPO SIGNALING PATHWAY IS HIGHLY CONSERVED AND COORDINATES TISSUE GROWTH WITH MORPHOGENESIS IN ANIMAL DEVELOPMENT. HIPPO SIGNALING ALSO HAS A COMPLEX RELATIONSHIP WITH APICAL-BASAL POLARITY IN EPITHELIAL CELLS - DISRUPTIONS IN HIPPO SIGNALING RESULT IN A LARGER APICAL DOMAIN AND DISRUPTIONS OF APICAL POLARITY AFFECT HIPPO SIGNALING. IN POLARIZED EPITHELIA CELLS, MANY HIPPO PATHWAY COMPONENTS - CRUMBS, EXPANDED, KIBRA, MERLIN AND WARTS - ARE APICALLY LOCALIZED. HOW UPSTREAM PATHWAY COMPONENTS ARE ACTIVATED AND INTERACT WITH POLARITY DETERMINANTS IS NOT WELL UNDERSTOOD. I PROPOSE TO RIGOROUSLY STUDY HOW MERLIN AND KIBRA INTERACT TO REGULATE THE HIPPO PATHWAY, AND HOW THIS INTERACTION IS CONNECTED TO APICAL POLARITY. WORK FROM OUR LAB HAS SHOWN THAT MERLIN AND KIBRA WORK TOGETHER TO PROMOTE HIPPO SIGNALING, WHILE THE PAN LAB HAS PROPOSED THAT MERLIN AND KIBRA ACT INDEPENDENTLY TO ACTIVATE THE HIPPO PATHWAY. APKC, A MAJOR REGULATOR OF APICAL POLARITY, INHIBITS KIBRA'S ABILITY TO ACT IN THE HIPPO PATHWAY AND INFLUENCES KIBRA AND MERLIN'S SUBCELLULAR LOCALIZATION. TOGETHER THESE STUDIES SUGGEST FUNCTIONAL INTERACTIONS BETWEEN APICAL POLARITY PROTEINS, MERLIN, AND KIBRA ARE IMPORTANT FOR REGULATION OF HIPPO-MEDIATED GROWTH CONTROL. IN THIS PROPOSAL, I PLAN TO ASK: 1) DO MERLIN AND KIBRA FUNCTION BOTH SEPARATELY AND TOGETHER IN THE HIPPO PATHWAY? AND 2) WHAT IS THE RELATIONSHIP BETWEEN APICAL POLARITY IN REGULATING KIBRA AND MERLIN LOCALIZATION AND HIPPO PATHWAY ACTIVITY? THESE STUDIES WILL BE CONDUCTED IN DROSOPHILA EPITHELIAL TISSUES SINCE DROSOPHILA HAVE SOPHISTICATED GENETIC, MOLECULAR, AND CELLULAR METHODS, AND HAVE BEEN WIDELY USED TO STUDY THE HIPPO PATHWAY AND APICAL POLARITY. FINDINGS FROM THIS WORK WILL PROVIDE NOVEL MOLECULAR INSIGHTS INTO HOW MERLIN AND KIBRA FUNCTION AS TUMOR SUPPRESSOR PROTEINS THROUGH REGULATION OF THE HIPPO PATHWAY. $0 6/8/26 Not listed UNDERSTANDING THE FUNCTION OF MERLIN AND KIBRA IN PROMOTING HIPPO PATHWAY ACTIVATION - ABSTRACT THE HIPPO SIGNALING PATHWAY IS HIGHLY CONSERVED AND COORDINATES TISSUE GROWTH WITH MORPHOGENESIS IN ANIMAL DEVELOPMENT. HIPPO SIGNALING ALSO HAS A COMPLEX RELATIONSHIP WITH APICAL-BASAL POLARITY IN EPITHELIAL CELLS - DISRUPTIONS IN HIPPO SIGNALING RESULT IN A LARGER APICAL DOMAIN AND DISRUPTIONS OF APICAL POLARITY AFFECT HIPPO SIGNALING. IN POLARIZED EPITHELIA CELLS, MANY HIPPO PATHWAY COMPONENTS - CRUMBS, EXPANDED, KIBRA, MERLIN AND WARTS - ARE APICALLY LOCALIZED. HOW UPSTREAM PATHWAY COMPONENTS ARE ACTIVATED AND INTERACT WITH POLARITY DETERMINANTS IS NOT WELL UNDERSTOOD. I PROPOSE TO RIGOROUSLY STUDY HOW MERLIN AND KIBRA INTERACT TO REGULATE THE HIPPO PATHWAY, AND HOW THIS INTERACTION IS CONNECTED TO APICAL POLARITY. WORK FROM OUR LAB HAS SHOWN THAT MERLIN AND KIBRA WORK TOGETHER TO PROMOTE HIPPO SIGNALING, WHILE THE PAN LAB HAS PROPOSED THAT MERLIN AND KIBRA ACT INDEPENDENTLY TO ACTIVATE THE HIPPO PATHWAY. APKC, A MAJOR REGULATOR OF APICAL POLARITY, INHIBITS KIBRA'S ABILITY TO ACT IN THE HIPPO PATHWAY AND INFLUENCES KIBRA AND MERLIN'S SUBCELLULAR LOCALIZATION. TOGETHER THESE STUDIES SUGGEST FUNCTIONAL INTERACTIONS BETWEEN APICAL POLARITY PROTEINS, MERLIN, AND KIBRA ARE IMPORTANT FOR REGULATION OF HIPPO-MEDIATED GROWTH CONTROL. IN THIS PROPOSAL, I PLAN TO ASK: 1) DO MERLIN AND KIBRA FUNCTION BOTH SEPARATELY AND TOGETHER IN THE HIPPO PATHWAY? AND 2) WHAT IS THE RELATIONSHIP BETWEEN APICAL POLARITY IN REGULATING KIBRA AND MERLIN LOCALIZATION AND HIPPO PATHWAY ACTIVITY? THESE STUDIES WILL BE CONDUCTED IN DROSOPHILA EPITHELIAL TISSUES SINCE DROSOPHILA HAVE SOPHISTICATED GENETIC, MOLECULAR, AND CELLULAR METHODS, AND HAVE BEEN WIDELY USED TO STUDY THE HIPPO PATHWAY AND APICAL POLARITY. FINDINGS FROM THIS WORK WILL PROVIDE NOVEL MOLECULAR INSIGHTS INTO HOW MERLIN AND KIBRA FUNCTION AS TUMOR SUPPRESSOR PROTEINS THROUGH REGULATION OF THE HIPPO PATHWAY. $50.1k 6/8/26