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CDK Signaling Pathway

Figure 1. CDK signaling pathway.

CDK overview

The transition between different states of the eukaryotic cell cycle is mainly controlled by checkpoints, which consist of two protein families: cyclin-dependent protein kinase (CDK) and cycling. The former monomer has no enzymatic activity and can only be activated when it forms a CDK-cyclin complex with the latter. A series of events associated with cell state transitions in the cell cycle are then initiated by specifically phosphorylating specific serine and threonine residues on the target protein. The latter is a class of proteins that aggregate and degrade in the cell cycle as cells change, and they regulate their activity by forming complexes with CDK, which are essential for CDK expression activity. The aggregation, activation, and depolymerization of the periodic CDK-cyclin complex are critical events driving cell cycle cell turnover. The regulation of cyclin-dependent protein kinase activation and inactivation is central to the control of the cell cycle.

CDK family

CDK is a class of cyclin-dependent protein kinases, and the substrate is a heterodimeric silk/threonine kinase family. So far, the named CDKS family has 13 members: CDK1~CDK13. CDK is activated by binding to cyclins, which catalyze the phosphorylation of substrates and drive the phase of the cell cycle to complete DNA synthesis and mitosis, leading to cell growth and proliferation. At the same time, CDKs can also play a negative regulatory role in combination with CDKs inhibitory factor (CKI), inhibit cell cycle progression and prevent cell division. In the different cell cycle phases, the main controlling G1 phase is CDK2, 4 and 6, and the S phase and G2 phase are dependent on CDK2, while the M phase is mainly regulated by CDK1. In view of the important role of CDK2 activity abnormality in tumorigenesis and development, CDK2 inhibitors have become a new direction in tumor treatment research. Studies have shown that direct inhibition of CDK2 kinase activity or inhibition of CDK2 by enhancing p27 and p21 can cause growth inhibition of ovarian cancer cells. Cyclin is a family of positive regulatory proteins and is an active factor of CDK. There are currently 8 types of Cyclin that have been found, which are classified into A, B, C, D, E, F, G and H. Cyclin mainly forms a Cyclin-CDK complex with CDK in cell cycle regulation, thereby activating CDK activity. For example, Cyclin D and CDK 4/6 complex control cells cross the G0/G1 phase, Cyclin E and CDK2 complex control cells from G0/ G1 entering S phase, Cyclin A and CDK2 complex control cells undergoing DNA synthesis in S phase, and Cyclin B forms a complex with CDK1 to control cells into G2/M phase. Among the cyclins, Cyclin D and cyclin E are the most studied. Cyclin mainly includes CyclinD1, D2, and D33 subtypes, of which cyclinD1 is the main subtype, also known as parathyroid adenoma gene-1, which is a key protein regulating G1 phase, mainly composed of CDK4/CDK6 synthase. The cell passes through the G1 phase, and the downstream substrate of CyclinD1-CDK4/CDK6 is the retinal membrane blastoma protein (Rb) and the transcription factor E2F. Yang et al found that Cyclin D1 is highly expressed in breast cancer and is expressed along with the progression of breast cancer. Increased expression of cyclin D1 is related to the formation and metastasis of breast cancer; similar findings have been found in cervical cancer, endometrial cancer, multiple myeloma, etc. And some studies have found cyclin in liver cancer and non-small cell lung cancer. The overexpression results of cyclin D1 are consistent.

CDK signaling pathway

  1. CDK signaling pathway cascade
  2. The conduction of the CDK signaling pathway begins with the binding of CDK and cyclin. The downstream substrate E2F of cyclinD1-CDK4/CDK6 promotes the transcription of cyclin E gene. Cyclin E binds to CDK2 and activates CDK2 to form a cyclin E-CDK2 complex, which phosphorylates pRb and P107. The downstream substrate regulates the cells to enter the S phase. The expression of Cyclin E is also regulated by ubiquitination of the SCF (SKP1-CUL1F box-protein) complex. The Chinese Institute of Microbiology found a new interaction between Cyclins/CDKs, the protein and Ankrd17, the substrate for Cyclin E/CDK2, a positive regulatory protein in the G1/S phase transition. The overexpression of Ankrd17 promotes cell entry into S phase, while decreased expression of Ankrd17 will inhibit DNA replication, prevent cell cycle progression and up-regulate p53 and p21 expression. Du et al found that the occurrence of breast tumors in Myc transgenic mice was associated with overexpression of Cyclin E. In human breast cancer cells, breast cancer patients with high expression of Cyclin E were also found to have a higher malignancy in non-small cell lung cancer and gastrointestinal tract. High expression of Cyclin E was also found in cancer. These findings suggest that Cyclin E is closely related to tumorigenesis.

  3. Pathway regulation
  4. The regulation of CDK signaling pathway can be mainly divided into positive regulation and negative regulation. Positive regulation of CDK phosphorylation: in the amino acid sequence of CDK, there are conserved threonine residues (position 161 of somatic CDC2; CDK2 160 bit). This residue is hidden in the T loop. After phosphorylation, the structure of the T-ring changes, thereby increasing the affinity of cyclin for CDK and making the CDK complex highly active. CDK7 binds to cyclin H and another small subunit and is phosphorylated at the 170th threonine residue, thereby having the ability to phosphorylate other CDK. Negative regulation of CDK phosphorylation: Inhibition of CDK complex activity can be accomplished by disrupting binding to cyclin and dephosphorylation of the threonine site. Experiments have shown that in addition to CDK 4, simultaneous phosphorylation at the 14th threonine residue and the 15th tyrosine residue can also inhibit the activity of the CDK complex. Both residues are located near the ATP junction site. Their phosphorylation affects the attachment of phosphoric acid to ATP. In fission yeast, Weel and Mik1 are likely to be kinases of tyrosine residues, and Nim1 /Cdr1 phosphorylates Weel inhibits its activity. To de-phosphorize the negative effects, CDC25 is required to dephosphorylate the two sites. CDC2, MAP, MAM 2 kinase phosphorylation of CDC25 N-terminal increases CDC25 activity. At the same time, PP1, PP2A can dephosphorylate CDCD25. It is not difficult to see that this is a network of phosphatase and kinase. In addition, some CDK inhibitors can effectively inhibit the conduction of CDK signaling pathway. In recent years, a batch of eggs that can be combined with CDK for one week has been isolated. The white complexes specifically bind to and inhibit the activity of the protein called the weekly protein-dependent enzyme to inhibit the protein. The confirmed proteins are FARI, p40 (slel / s DB25) and PHOsl, which are inhibited separately. Kinase activity of CDC28-CLN, CDC28-CLB and PHO 85-PHO8 complexes; p21(CIPI / WAF / CAPZO / SDI), P27(KIP in mammals), p16 , NK , and p15NK4β, which inhibit the activity of CDKZ-cyclin, CDK4 -cyclin, CDK4-cyclin and CDK6-cyclin complex, respectively. The mechanism by which CKI regulates C D K is unclear. However, there is evidence that they may directly affect the activity of the enzyme by affecting the binding of the enzyme to the substrate. For example, FARI p4. P21 can be phosphorylated by its target CDK-period protein complex, and p40 reduces the Vmax and Km of its target CDC 28 - CLB complex combined with the substrate. Although most CKIs are more susceptible to recognizing the CDK-cyclin complex and are less likely to recognize monomeric CDK, p16IN4K binds to CDK 4 monomers in vivo, so by blocking CDK 4 the binding of the protein is inhibited. The inhibition of c D K activity by CKI may be an important factor in cell cycle regulation. Because the regulation of CKI level is complex and related to the tumor suppressor gene p53, the second messenger cAMP and the transforming growth factor TGF, the activity regulation of CDK and the response of the cell response environment are changed. Linkages align cell transitions in the cell cycle with environmental changes. Some of the regulation of CKI is carried out at the transcriptional level. For example, when DNA is damaged or cell ages, p53 induces transcription of p21 and blocks the cell cycle. As in human keratinocytes, the conversion growth factor TGFβ enhances the expression of the p15NK4β gene. The regulation of CKI can also be carried out at the post-translational level. For example, the total 2P7 content in the epidermal cells of the leech is unchanged in the cell cycle and is not affected by the TGF. However, when the TGF is treated, the p27 is a CDK-cyclin. The inhibitory effect of the complex is increased, and the treatment of TGF may cause 2P7 to be released from a bound state.

  5. Relationship with disease
  6. Senescence

    Studies have shown that although the total phosphorylation level of CDK2 is unchanged in senescent cells, the phosphorylation levels in cyclin D, E, and CDK are decreased, resulting in cell arrest in the G1 phase. Furthermore, senescent cells do not have mRNA and products of cyclin A, cyclin B, CDK4, and CDC 2. In addition, there may be no mature mRNA and products of PCN A due to the lack of post-transcriptional regulation. At the same time, the expression of P21 in senescent cells is 20 times higher than that of normal proliferating young cells, which may be the cause of cell senescence and cell cycle delay.

    Gastric cancer

    Studies have pointed out that CDK5 expression is an independent factor in the evaluation of prognosis in patients with gastric cancer. The 5-year survival rate of patients increases with the increase in CDK5 expression in cancer tissues. In the diagnosis and treatment of gastric cancer, CDK5 protein is expected to become a target.

References:

  1. Pope P A, Bhaduri S, Pryciak P M. Regulation of cyclin-substrate docking by a G1 arrest signaling pathway and the Cdk inhibitor Far1. Current Biology. 2014, 24(12):1390-6.
  2. Cai W S, Shen F, Feng Z, et al. Downregulation of CDK-8 inhibits colon cancer hepatic metastasis by regulating Wnt/β-catenin pathway. Biomedicine & Pharmacotherapy. 2015, 74:153-157.
  3. Depaoli H C, Goldman G H, Goldman M H. SCI1, the first member of the tissue-specific inhibitors of CDK (TIC) class, is probably connected to the auxin signaling pathway. Plant Signaling & Behavior. 2012, 7(1):53-8.
  4. Mcgrath D A, Balog E R M, Kõivomägi M, et al. Cks Confers Specificity to Phosphorylation-Dependent Cdk Signaling Pathways. Nature Structural & Molecular Biology. 2013, 20(12):1407-1414.
  5. Berrak O, Arisan E D, Obakan-Yerlikaya P, et al. mTOR is a finetuning molecule in CDK inhibitors-induced distinct cell death mechanisms via PI3K/AKT/mTOR signaling axis in prostate cancer cells. Apoptosis. 2016, 21(10):1-21.

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