Project Grant F31CA310713

REGULATION OF ENDOGENOUS CEREBLON SUBSTRATE DEGRADATION BY PI3K SIGNALING IN CANCER - PROJECT SUMMARY CEREBLON (CRBN) IS AN E3 LIGASE SUBSTRATE ADAPTER AND THE PRIMARY TARGET OF THALIDOMIDE AND LENALIDOMIDE, THERAPEUTICS USED TO TREAT MULTIPLE MYELOMA. THESE THERAPEUTICS REPROGRAM CRBN TO DEGRADE DISEASE-RELEVANT PROTEINS BUT MAY ALSO CAUSE OFF-TARGET TOXICITIES BY INTERFERING WITH CRBN'S NATIVE FUNCTION. HOWEVER, THE NATIVE FUNCTION AND REGULATION OF CRBN REMAIN POORLY UNDERSTOOD. OUR RECENT WORK HAS SHOWN THAT CRBN RECOGNIZES ENDOGENOUS SUBSTRATE PROTEINS BEARING THE C-TERMINAL CYCLIC IMIDE POST-TRANSLATIONAL MODIFICATION, WHICH IS INSTALLED BY THE ENZYME PROTEIN CARBOXYMETHYLTRANSFERASE (PCMT1). THIS DEFINES A NEW PROTEIN DEGRADATION PATHWAY IN WHICH PCMT1 MODIFIES SUBSTRATE PROTEINS TO ENABLE THEIR RECOGNITION AND DEGRADATION BY CRBN. ONE SUCH SUBSTRATE IS GLUTAMINE SYNTHETASE (GLUL), A KEY METABOLIC ENZYME THAT IS LINKED TO TUMORIGENESIS WHEN DYSREGULATED. THIS FINDING OPENS NEW AVENUES FOR EXPLORATION OF HOW THIS PATHWAY IS REGULATED AND HOW IT IMPACTS CELLULAR PHYSIOLOGY AND DISEASE. OUR PRELIMINARY STUDIES SHOW THAT INHIBITING PHOSPHOINOSITIDE 3-KINASE (PI3K), A CENTRAL REGULATOR OF GROWTH AND METABOLISM, ACCELERATES GLUL DEGRADATION THROUGH THIS PCMT1-CRBN PATHWAY. THIS REVEALS A NOVEL CONNECTION BETWEEN THE PI3K SIGNALING PATHWAY AND PCMT1/CRBN-MEDIATED PROTEIN DEGRADATION. NOTABLY, PI3K IS AMONG THE MOST FREQUENTLY MUTATED ONCOGENES IN CANCER, AND DEFECTS IN PI3K, PCMT1, CRBN, AND GLUL HAVE ALL BEEN LINKED TO NEUROLOGICAL DISORDERS. THUS, BETTER UNDERSTANDING THIS PATHWAY MAY EXPLAIN THE SIDE EFFECTS OF CRBN-TARGETING CANCER DRUGS AND REVEAL NEW MECHANISMS IN TUMOR PROGRESSION. THIS PROJECT WILL DEFINE HOW PI3K SIGNALING REGULATES THE PCMT1-CRBN DEGRADATION PATHWAY AND HOW THIS REGULATION IS DISRUPTED BY CANCER-ASSOCIATED MUTATIONS AND CLINICAL THERAPEUTICS. IN AIM 1, I WILL INVESTIGATE THE MOLECULAR MECHANISM BY WHICH PI3K SIGNALING REGULATES GLUL DEGRADATION AND WHETHER THE TURNOVER OF ADDITIONAL SUBSTRATE PROTEINS IS SIMILARLY CONTROLLED. IN AIM 2, I WILL EXAMINE HOW ONCOGENIC PI3K MUTATIONS AND CRBN-TARGETING DRUGS ALTER THIS PATHWAY, AND HOW THESE DISRUPTIONS AFFECT CELLULAR METABOLISM. THIS WORK WILL ILLUMINATE A PREVIOUSLY UNRECOGNIZED REGULATORY PATHWAY AND MAY REVEAL STRATEGIES TO REDUCE TOXICITY FROM CRBN-TARGETING THERAPEUTICS AND TO DEVELOP IMPROVED TREATMENTS OF PI3K-DRIVEN CANCERS.