S phase kinase-associated protein 1 (SKP1)–cullin 1 (CUL1)–F-box protein (SCF) ubiquitin ligase complexes use a family of F-box proteins as substrate adaptors to mediate the degradation of a large number of regulatory proteins involved in diverse processes. The dysregulation of SCF complexes and their substrates contributes to multiple pathologies. In the 14 years since the identification and annotation of the F-box protein family, the continued identification and characterization of novel substrates has greatly expanded our knowledge of the regulation of substrate targeting and the roles of F-box proteins in biological processes. Here, we focus on the evolution of our understanding of substrate recruitment by F-box proteins, the dysregulation of substrate recruitment in disease and potential avenues for F-box protein-directed disease therapies.
Summary The recent clinical successes of inhibitors of the proteasome for the treatment of cancer have highlighted the therapeutic potential of this protein degradation system. Proteasome inhibitors prevent the degradation of numerous proteins, so increased specificity could be achieved by inhibiting the components of the ubiquitin-proteasome system that target specific subsets of proteins for degradation. F-box proteins are the substrate-targeting subunits of SKP1-CUL1-F-box protein (SCF) ubiquitin ligase complexes. Through the degradation of a plethora of diverse substrates, SCF ubiquitin ligases control a large number of processes at the cellular and organismal levels, and their misregulation is implicated in many pathologies. SCF ligases are characterized by a high specificity for their substrates, so they represent promising drug targets. However, the potential for therapeutic manipulation of SCF complexes remains an underdeveloped area. This review will explore and discuss potential strategies to target SCF-mediated biology to treat human diseases.
DEPTOR is a recently identified inhibitor of the mTOR kinase that is highly regulated at the posttranslational level. In response to mitogens, we found that DEPTOR was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the F-box protein βTrCP, with consequent proteasomal degradation of DEPTOR. Phosphorylation of the βTrCP degron in DEPTOR is executed by CK1α, after a priming phosphorylation event mediated by either the mTORC1 or mTORC2 complexes. Blocking the βTrCP-dependent degradation of DEPTOR via βTrCP knockdown or expression of a stable DEPTOR mutant that is unable to bind βTrCP results in mTOR inhibition. Our findings reveal that mTOR cooperates with CK1α and βTrCP to generate an auto-amplification loop to promote its own full activation. Moreover, our results suggest that pharmacologic inhibition of CK1 may be a viable therapeutic option for the treatment of cancers characterized by activation of mTOR signaling pathways.
Cul1, a member of the cullin ubiquitin ligase family, forms a multiprotein complex known as SCF and plays an essential role in numerous cellular and biological activities. A Cul1 homologue, p185 (Cul7), has been isolated as an simian virus 40 large T antigen-binding protein. To understand the physiological role of p185, we generated mice lacking p185. p185 ؊/؊ embryos are runted and die immediately after birth because of respiratory distress. Dermal and hypodermal hemorrhage is detected in mutant embryos at late gestational stage. p185 ؊/؊ placentas show defects in the differentiation of the trophoblast lineage with an abnormal vascular structure. We demonstrate that p185 forms an SCF-like complex with Skp1, Rbx1, Fbw6 (Fbx29), and FAP68 (FAP48, glomulin). FAP68 has recently been identified as a gene responsible for familial glomuvenous malformation. These results suggest that p185 forms a multiprotein complex and plays an important role in vascular morphogenesis.T he rapid destruction of regulatory proteins by ubiquitinmediated proteolysis plays an important role in various biological processes. Protein ubiquitination is carried out by the sequential action of three enzymes, namely E1, E2, and E3 (1). E3 ubiquitin ligases determine the specificity of the substrate protein, and it is likely that protein ubiquitination in vivo is controlled primarily by regulating E3 activity or E3-substrate interaction (2). The Skp1-Cul1-F-box (SCF) complex is a well characterized E3 ubiquitin ligase that plays an essential role in a wide variety of activities, including cell cycle control (3, 4), muscle atrophy (5, 6), and protein quality control (7). To date, the human cullin protein family consists of six members: CUL1, CUL2, CUL3, CUL4A, CUL4B, and CUL5 (8). Although the physiological function of each cullin protein is largely unknown, mouse knockout evidence has demonstrated their biological significance. Cul1-, Cul3-, and Cul4A-deficient mice show early embryonic lethality (9-12), indicating their crucial role in early mammalian development.F box proteins are the variable subunits of the SCF complex, and a large number of human F box proteins have been reported (13,14). F box proteins contain an F box motif that binds to Skp1 and a carboxyl-terminal domain that specifies association with substrate proteins (15,16). SCF targets a number of different substrate proteins by associating with specific F box proteins (16,17). Among the human cullin proteins, SKP1 protein has been reported to bind specifically to CUL1 (18). Degradation of some F box proteins, such as Cdc4, Grr1, and SKP2 (22) in humans, are mediated by the SCF complex itself.Simian virus 40 large T antigen transforms a variety of rodent cells in vitro and in vivo. p185 (KIAA0076, p193, Cul7) was isolated as an simian virus 40 large T antigen-associated protein in murine cells (23,24). Although it has been reported that overexpression of p185 induces apoptosis in NIH 3T3 cells (24), the biological and molecular functions of p185 remain unclear. Here we demonstrate ...
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