Role of SCF complex in cell cycle
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
E1 Ub-activating enzyme (e.g. ubiquitin-activating enzyme E1
(UBE1)) activates Ubiquitin in
the ATP-dependent manner  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 . E3 Ub-ligase mediates the transfer of
Ubiquitin from E2 Ub-conjugating enzyme to the substrate
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 . 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 .
F-box proteins directly recruit ubiquitination substrates and bridge the interaction
between E2 Ub-conjugating enzyme and the substrate .
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 .
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 , .
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 . Stimulation of the
growth factor beta (TGF-beta)/ SMAD family member 3 (Smad3)
pathway promotes SCF complex-mediated
CDC25A ubiquitination .
Moreover, SCF complex may
promote ubiquitin-proteasome degradation of
Phosphorylated by cyclin-dependent kinases (e.g. cyclin-dependent kinase 4
(CDK4)) p130 is ubiquitinated
by SCF complex in G1 phase .
CDK2 binds to SCF complex
and is degraded during late S or G2 phase. At the same time,
phosphorylation of p27KIP1 ,
Cyclin E  and Cdt1
 by CDK2 promotes their
SCF complex-mediated destruction during G1 and S phases
. Ubiquitination of p27KIP1 requires the
SCF complex and Skp2 F-box binding protein
CKS1 . SKP2 and
CKS1 are negatively regulated by Anaphase-promoting/ cell
division cycle 20 related 1 protein complex
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 , .
Cyclin D1  and
p21 bind to the SCF complex and
get degraded during interphase too .
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  and Emi1 , . The
phosphorylation makes WEE1 and
to SCF complex-mediated
degradation. Emi1 promotes S
phase entry in somatic cells by inhibiting the APC/hCdh1
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