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Cyclin-dependent kinase 4
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Cyclin-dependent kinase 4
Cyclin-dependent kinase 4 (CDK4), also known as cell division protein kinase 4, is an enzyme that is encoded by the CDK4 gene in humans. CDK4 is a member of the cyclin-dependent kinase family, a group of serine/threonine kinases which regulate the cell cycle. CDK4 regulates the G1/S transition by contributing to the phosphorylation of retinoblastoma (RB) protein, which leads to the release of protein factors like E2F1 that promote S-phase progression. It is regulated by cyclins like cyclin D proteins, regulatory kinases, and cyclin kinase inhibitors (CKIs). Dysregulation of the CDK4 pathway is common in many cancers, and CDK4 is a new therapeutic target in cancer treatment.
The CDK4 gene is located on chromosome 12 in humans. The gene is composed of 4,583 base pairs which together code for the 303 amino acid protein with a molecular mass of 33,730 Da. All CDK proteins, including CDK4, have two lobes: the smaller N-terminal lobe (which contains an inhibitory G-loop), and the C terminal lobe (which contains an activation domain and a T-loop). Between these two lobes is the serine/threonine kinase domain where ATP binds. In its completely inactive form, CDK4's T-loop blocks the ATP binding site, and the surrounding amino acid side chains prevent ATP binding. The kinase's activity increases when it dimerizes with the corresponding cyclin, cyclin D, which causes a conformational change at the ATP binding site. CDK activating kinase (CAK) then phosphorylates the T172 site (located on the T-loop). These two actions move the T-loop out of the active ATP-binding site and make ATP binding more favorable.
Notably, CDK6 is very related to CDK4 in both structure and function. They share 71% of their amino acids and both regulate the G1/S transition by phosphorylating Rb. CDK4 and 6 differ in their cellular localization and other off-pathway roles, however are commonly referred together as CDK4/6.
The CDK4 protein is similar to the fungi gene products of S. cerevisiae cdc28 and S. pombe cdc2.
CDK4 is the catalytic subunit of the protein-kinase complex CDK4-cyclin D, which plays a role in G1/S cell cycle progression. During G1 phase, the cell grows and prepares for the DNA replication that occurs in the S phase. There is a G1/S checkpoint which acts as a committed step to enter S-phase. This checkpoint ensures that cells moving toward mitosis are large enough and do not have DNA damage that could be passed on to daughter cells.
There are two models of CDK4 cell cycle regulation. The older model proposes that the kinase is responsible for the phosphorylation of retinoblastoma gene product (Rb). The Ser/Thr-kinase component of cyclin D-CDK4 (DC) forms complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G1/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G1 phase. In this model, CDK4 inhibits Rb, which inhibits E2F, which promotes progression into S phase.
The newer model, as proposed in a 2014 paper by Narasimha et al., The CDK4-cyclin D complex phosphorylates the retinoblastoma tumor suppressor protein (Rb) and its related proteins p107 and p130, which go on to inhibit cell cycle progression. As a kinase, the CDK4 serine/threonine active site converts ATP to ADP and transfers the removed phosphate group to Rb. Rb is mono-phosphorylated in early G1 by the CDK4-cyclin D complex. When mono-phosphorylated, Rb exists as one of the 14 isoforms, which bind to protein factors like E1a, and proteins in the E2F family.
The new model of CDK4 regulation posits that at the G1/S checkpoint, if a cell seems healthy, CDK2 (a different cyclin dependent kinase) inactivates Rb, and these protein factors are released back into the cell. E2F proteins then activate the transcription of genes that cause S-phase progression. However, if at the G1/S checkpoint a cell detects DNA damage, it will respond by activating the CDK4-cyclin D complex to mono-phosphorylate, and activate Rb. This prevents Rb from dissociating from E2F proteins, which prevents them from activating the transcription of the S-phase progression genes.
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Cyclin-dependent kinase 4
Cyclin-dependent kinase 4 (CDK4), also known as cell division protein kinase 4, is an enzyme that is encoded by the CDK4 gene in humans. CDK4 is a member of the cyclin-dependent kinase family, a group of serine/threonine kinases which regulate the cell cycle. CDK4 regulates the G1/S transition by contributing to the phosphorylation of retinoblastoma (RB) protein, which leads to the release of protein factors like E2F1 that promote S-phase progression. It is regulated by cyclins like cyclin D proteins, regulatory kinases, and cyclin kinase inhibitors (CKIs). Dysregulation of the CDK4 pathway is common in many cancers, and CDK4 is a new therapeutic target in cancer treatment.
The CDK4 gene is located on chromosome 12 in humans. The gene is composed of 4,583 base pairs which together code for the 303 amino acid protein with a molecular mass of 33,730 Da. All CDK proteins, including CDK4, have two lobes: the smaller N-terminal lobe (which contains an inhibitory G-loop), and the C terminal lobe (which contains an activation domain and a T-loop). Between these two lobes is the serine/threonine kinase domain where ATP binds. In its completely inactive form, CDK4's T-loop blocks the ATP binding site, and the surrounding amino acid side chains prevent ATP binding. The kinase's activity increases when it dimerizes with the corresponding cyclin, cyclin D, which causes a conformational change at the ATP binding site. CDK activating kinase (CAK) then phosphorylates the T172 site (located on the T-loop). These two actions move the T-loop out of the active ATP-binding site and make ATP binding more favorable.
Notably, CDK6 is very related to CDK4 in both structure and function. They share 71% of their amino acids and both regulate the G1/S transition by phosphorylating Rb. CDK4 and 6 differ in their cellular localization and other off-pathway roles, however are commonly referred together as CDK4/6.
The CDK4 protein is similar to the fungi gene products of S. cerevisiae cdc28 and S. pombe cdc2.
CDK4 is the catalytic subunit of the protein-kinase complex CDK4-cyclin D, which plays a role in G1/S cell cycle progression. During G1 phase, the cell grows and prepares for the DNA replication that occurs in the S phase. There is a G1/S checkpoint which acts as a committed step to enter S-phase. This checkpoint ensures that cells moving toward mitosis are large enough and do not have DNA damage that could be passed on to daughter cells.
There are two models of CDK4 cell cycle regulation. The older model proposes that the kinase is responsible for the phosphorylation of retinoblastoma gene product (Rb). The Ser/Thr-kinase component of cyclin D-CDK4 (DC) forms complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G1/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G1 phase. In this model, CDK4 inhibits Rb, which inhibits E2F, which promotes progression into S phase.
The newer model, as proposed in a 2014 paper by Narasimha et al., The CDK4-cyclin D complex phosphorylates the retinoblastoma tumor suppressor protein (Rb) and its related proteins p107 and p130, which go on to inhibit cell cycle progression. As a kinase, the CDK4 serine/threonine active site converts ATP to ADP and transfers the removed phosphate group to Rb. Rb is mono-phosphorylated in early G1 by the CDK4-cyclin D complex. When mono-phosphorylated, Rb exists as one of the 14 isoforms, which bind to protein factors like E1a, and proteins in the E2F family.
The new model of CDK4 regulation posits that at the G1/S checkpoint, if a cell seems healthy, CDK2 (a different cyclin dependent kinase) inactivates Rb, and these protein factors are released back into the cell. E2F proteins then activate the transcription of genes that cause S-phase progression. However, if at the G1/S checkpoint a cell detects DNA damage, it will respond by activating the CDK4-cyclin D complex to mono-phosphorylate, and activate Rb. This prevents Rb from dissociating from E2F proteins, which prevents them from activating the transcription of the S-phase progression genes.
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