SKP2
Encyclopedia
S-phase kinase-associated protein 2 is an enzyme
that in humans is encoded by the SKP2 gene
.
family which is characterized by an approximately 40 amino acid
motif, the F-box domain. The F-box protein
s constitute one of the four subunits of ubiquitin
protein ligase complex called SCFs (SKP1
-cullin
-F-box
), which often—but not always—recognize substrates in a phosphorylation
-dependent manner. The F-box proteins are divided into three classes: Fbxws containing WD40 repeat
domains, Fbxls containing leucine-rich repeat
s, and Fbxos containing either different protein–protein interaction modules or no recognizable motifs
. The protein encoded by this gene belongs to the Fbxls class; in addition to an F-box, this protein contains 10 tandem
leucine-rich repeats. Alternative splicing of this gene generates 2 transcript variants encoding different isoforms.
Skp2 forms a stable complex with the cyclin A
-CDK2
S-phase kinase
. It specifically recognizes and promotes the degradation of phosphorylated cyclin-dependent kinase inhibitor 1B (CDKN1B
, also referred to as p27 or KIP1) predominantly in S, G2, and the initial part of the M phase.
The degradation of p27 via Skp2 requires the accessory protein CKS1B
. To prevent premature degradation of p27, Skp2 levels are kept low during early and mid-G1 due to the APC/CCdh1ubiquitin ligase, which mediates the ubiquitylation of Skp2.
Phosphorylation of Ser64 and, to a lesser extent, Ser72 of Skp2 contributes to the stabilization of Skp2 by preventing its association with APC/CCdh1; however, Skp2 phosphorylation on these residues is dispensable for its subcellular localization and for Skp2 assembly into an active SCF ubiquitin ligase.
of lymphomas. Higher levels of Skp2 expression bode poorly for breast cancer
.
Skp2 is a potential target for pten
-deficient cancers.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the SKP2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
This gene encodes a member of the F-box proteinF-box protein
F-box proteins are proteins containing at least one F-box domain. The first identified F-box protein is one of three components of the SCF complex, which mediates ubiquitination of proteins targeted for degradation by the proteasome....
family which is characterized by an approximately 40 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
motif, the F-box domain. The F-box protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s constitute one of the four subunits of ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
protein ligase complex called SCFs (SKP1
SKP1A
S-phase kinase-associated protein 1 is an enzyme that in humans is encoded by the SKP1 gene.This gene encodes a protein that is a member of the SCF ubiquitin ligase protein complex. It binds to F-box proteins , such as cyclin F, S-phase kinase-associated protein 2, and other regulatory proteins...
-cullin
CUL1
Cullin 1, also known as CUL1, is a human protein and gene from cullin family.This protein plays an important role in protein degradation and protein ubiquitination....
-F-box
F-box protein
F-box proteins are proteins containing at least one F-box domain. The first identified F-box protein is one of three components of the SCF complex, which mediates ubiquitination of proteins targeted for degradation by the proteasome....
), which often—but not always—recognize substrates in a phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
-dependent manner. The F-box proteins are divided into three classes: Fbxws containing WD40 repeat
WD40 repeat
The WD40 repeat is a short structural motif of approximately 40 amino acids , often terminating in a tryptophan-aspartic acid dipeptide...
domains, Fbxls containing leucine-rich repeat
Leucine-rich repeat
A leucine-rich repeat is a protein structural motif that forms an α/β horseshoe fold. It is composed of repeating 20–30 amino acid stretches that are unusually rich in the hydrophobic amino acid leucine...
s, and Fbxos containing either different protein–protein interaction modules or no recognizable motifs
Sequence motif
In genetics, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and has, or is conjectured to have, a biological significance...
. The protein encoded by this gene belongs to the Fbxls class; in addition to an F-box, this protein contains 10 tandem
Tandem
Tandem is an arrangement where a team of machines, animals or people are lined up one behind another, all facing in the same direction....
leucine-rich repeats. Alternative splicing of this gene generates 2 transcript variants encoding different isoforms.
Skp2 forms a stable complex with the cyclin A
Cyclin A
Cyclin A is a member of the cyclin family.Cyclin A binds to S phase Cdk2 and is required for the cell to progress through the S phase. Cyclin A/ Cdk2 is inhibited by the complex p21CIP.-External links:*...
-CDK2
Cyclin-dependent kinase 2
Cyclin-dependent kinase 2 also known as cell division protein kinase 2 is an enzyme that in humans is encoded by the CDK2 gene.-Function:...
S-phase kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
. It specifically recognizes and promotes the degradation of phosphorylated cyclin-dependent kinase inhibitor 1B (CDKN1B
CDKN1B
Cyclin-dependent kinase inhibitor 1B is an enzyme that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the Cip/Kip family of cyclin dependent kinase inhibitor proteins. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4...
, also referred to as p27 or KIP1) predominantly in S, G2, and the initial part of the M phase.
The degradation of p27 via Skp2 requires the accessory protein CKS1B
CKS1B
Cyclin-dependent kinases regulatory subunit 1 is a protein that in humans is encoded by the CKS1B gene.- Function :The CKS1B protein binds to the catalytic subunit of the cyclin-dependent kinases and is essential for their biological function...
. To prevent premature degradation of p27, Skp2 levels are kept low during early and mid-G1 due to the APC/CCdh1ubiquitin ligase, which mediates the ubiquitylation of Skp2.
Phosphorylation of Ser64 and, to a lesser extent, Ser72 of Skp2 contributes to the stabilization of Skp2 by preventing its association with APC/CCdh1; however, Skp2 phosphorylation on these residues is dispensable for its subcellular localization and for Skp2 assembly into an active SCF ubiquitin ligase.
Clinical significance
Skp2 behaves as an oncogene in cell systems and is an established protooncogene causally involved in the pathogenesisPathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of lymphomas. Higher levels of Skp2 expression bode poorly for breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
.
Skp2 is a potential target for pten
PTEN (gene)
Phosphatase and tensin homolog is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers....
-deficient cancers.
Interactions
SKP2 has been shown to interact with:- CCNA2Cyclin A2Cyclin-A2 is a protein that in humans is encoded by the CCNA2 gene.-Interactions:Cyclin A2 has been shown to interact with ITGB3BP, Retinoblastoma-like protein 1, E2F1, CDC6, SKP2 and Flap structure-specific endonuclease 1.-References:...
, - CDK2Cyclin-dependent kinase 2Cyclin-dependent kinase 2 also known as cell division protein kinase 2 is an enzyme that in humans is encoded by the CDK2 gene.-Function:...
, - CDKN1A
- CDKN1BCDKN1BCyclin-dependent kinase inhibitor 1B is an enzyme that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the Cip/Kip family of cyclin dependent kinase inhibitor proteins. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4...
- CKS1BCKS1BCyclin-dependent kinases regulatory subunit 1 is a protein that in humans is encoded by the CKS1B gene.- Function :The CKS1B protein binds to the catalytic subunit of the cyclin-dependent kinases and is essential for their biological function...
, - CDT1DNA replication factor CDT1DNA replication factor Cdt1 is a protein that in humans is encoded by the CDT1 gene.The protein encoded by this gene is a key licensing factor which, along with the protein Cdc6, functions to license DNA by forming the pre-replication complex...
, - CUL1CUL1Cullin 1, also known as CUL1, is a human protein and gene from cullin family.This protein plays an important role in protein degradation and protein ubiquitination....
- E2F1E2F1Transcription factor E2F1 is a protein that in humans is encoded by the E2F1 gene.-Interactions:E2F1 has been shown to interact with NCOA6, Retinoblastoma-like protein 1, Retinoblastoma protein, GTF2H1, SKP2, PURA, NPDC1, Sp2 transcription factor, Sp1 transcription factor, CUL1, ARID3A, TOPBP1,...
, - ORC1L, and
- SKP1ASKP1AS-phase kinase-associated protein 1 is an enzyme that in humans is encoded by the SKP1 gene.This gene encodes a protein that is a member of the SCF ubiquitin ligase protein complex. It binds to F-box proteins , such as cyclin F, S-phase kinase-associated protein 2, and other regulatory proteins...
.