Pathway maps

Cell cycle_Role of SCF complex in cell cycle regulation
Cell cycle_Role of SCF complex in cell cycle regulation

Object List (links open in MetaCore):

Chk1, RING-box protein 1, UBE1, CDC34, CDC25A, CKS1, Wee1, beta-TrCP, NEDD8, p27KIP1, Cul1/Rbx1 E3 ligase, APC/hCDH1 complex, Cdt1, PLK1, Cyclin E, CDK1 (p34), E2F1, Cyclin D1, Skp2/TrCP/ FBXW, SKP2, Ubiquitin, SKP1, Emi1, CDK4, p21, SMAD3, p130, Cullin 1, CDK2


Role of SCF complex in cell cycle regulation

The events controlling cell division are governed by the degradation of different regulatory proteins by the Ubiquitin -dependent pathway. Ubiquitin, a small protein of 76 amino acids is found in all eukaryotic cells. In the Ubiquitin -dependent pathway, the attachment of a polyubiquitin chain to a substrate is realized by an ubiquitin-ligase targets this substrate for degradation by the 26S proteasome. The ubiquitination pathway sequentially involves the E1 Ub-activating enzyme, E2 Ub-conjugating enzymes, and E3 Ub-ligases [1].

E1 Ub-activating enzyme (e.g. ubiquitin-activating enzyme E1 ( UBE1 )) activates Ubiquitin in the ATP-dependent manner [2] and transfers it to E2 Ub-conjugating enzyme through thioester bond formation. E2 Ub-conjugating enzyme (e.g. cell division cycle 34 ubiquitin-protein ligase ( CDC34 )) activates ubiquitin-polymerization [3]. E3 Ub-ligase mediates the transfer of Ubiquitin from E2 Ub-conjugating enzyme to the substrate protein [1].

S-phase kinase-associated protein 1 p19 ( SKP1 )/ Cullin/F-box complex ( SCF complex) is one of E3-ubiquitin ligases, which play a very important role in the cell cycle. SCF complex consists of Cullin 1, SKP1, F-box proteins (e.g. S-phase kinase-associated protein 2 p45 ( Skp2 ), beta-transducin repeat containing protein ( TrCP ) or F-box protein FBW7 ( FBXW7 )) and RING-box protein 1. The Cullin 1/ RING-box protein 1 components are associated with E2 Ub-conjugating enzymes [1]. Ubiquitin-lake protein NEDD8 charged surface residues mediates activation of Cullin 1/ RING-box protein 1, which is needed to specifically support Cdc34 -catalyzed ubiquitin polymerization [3]. F-box proteins directly recruit ubiquitination substrates and bridge the interaction between E2 Ub-conjugating enzyme and the substrate [1].

SCF complex participates in cell cycle regulation by stimulating ubiquitination of the cell cycle proteins and their degradation by the 26S proteasome. Most substrates require phosphorylation to interact with the F-box protein in an SCF complex [1].

Cell division cycle 25A phosphotase ( CDC25A ), Cyclin D, Cyclin E, cyclin-dependent kinase 2 ( CDK2 ), DNA replication factor ( Cdt1 ), cyclin-dependent kinase inhibitor 1A ( p21 ), cyclin-dependent kinase inhibitor 1B ( p27KIP1 ), E2F transcription factor 1 ( E2F1 ) and retinoblastoma-like 2 ( p130 ) bind to SCF complex and degrade during interphase [4], [1].

CDC25A is phosphorylated by some kinases in response to DNA damage (e.g. cell cycle checkpoint kinase 1 ( Chk1 ). Phosphorylated CDC25A is ubiquitinated by SCF complex in late S and G2 phases [5]. Stimulation of the growth factor beta (TGF-beta)/ SMAD family member 3 ( Smad3 ) pathway promotes SCF complex- mediated CDC25A ubiquitination [6]. Moreover, SCF complex may promote ubiquitin-proteasome degradation of Smad3 [7].

Phosphorylated by cyclin-dependent kinases (e.g. cyclin-dependent kinase 4 ( CDK4 )) p130 is ubiquitinated by SCF complex in G1 phase [8].

CDK2 binds to SCF complex and is degraded during late S or G2 phase. At the same time, phosphorylation of p27KIP1 [9], Cyclin E [10] and Cdt1 [11] by CDK2 promotes their SCF complex- mediated destruction during G1 and S phases [1]. Ubiquitination of p27KIP1 requires the SCF complex and Skp2 F-box binding protein CKS1 [12]. SKP2 and CKS1 are negatively regulated by Anaphase-promoting/ cell division cycle 20 related 1 protein complex ( APC/hCdh1 )-mediated ubiquitination. Targeting of SKP2 and CKS1 by APC/hCdh1 stabilizes p27KIP1, subsequently leading to the maintenance of G1 phase and blocking premature S-phase initiation [13], [14].

Cyclin D1 [15] and p21 bind to the SCF complex and get degraded during interphase too [16].

Tyrosine kinase Wee1 and F-box protein 5 ( Emi1 ) bind to SCF complex and degrade during mitosis.

Major M-phase kinases Polo-like kinase 1 ( Plk1 ) and Cdk1 phosphorylate WEE1 [17] and Emi1 [18], [19]. The phosphorylation makes WEE1 and Emi1 accessible to SCF complex- mediated degradation . Emi1 promotes S phase entry in somatic cells by inhibiting the APC/hCdh1 complex [20].


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