Protein kinases and phosphatases act as key cellular messengers that transfer information onto effector substrates. We are identifying the role of CRLs in the context of central kinase cascades that control cell proliferation and survival. Previous work in our lab has identified a major role for CRL1 complexes (aka, SCF ligases) in the proper regulation of the mTOR and the PI3-K pathways. Specifically, we described a role for β-TrCP in the destruction of the mTOR inhibitor Deptor, the Rsk1/2 target BimEL, and the S6K target PDCD4. We characterized the activity of FBXL2 in the regulation of the PI3-K regulatory subunit p85β and in the regulation of the ER-mitochondria calcium flux by targeting IP3R3 for degradation. We also studied the role of the TDH-GCN5L1-FBXO15-KBP axis in mitochondrial biogenesis and the role of the histone demethylase KDMA2 in repressing ribosomal RNA genes. Finally, we identified a novel atypical member of the prenyltransferase family and we are investigating its role in the response to mitogenic stimuli. Currently, we are interested in expanding our knowledge of how CRLs control the proper activation of the MAPK/ERK pathway, and the regulation of tyrosine kinases-mediated pathways.