CDK5
Description
The CDK5 (cyclin dependent kinase 5) is a protein-coding gene located on chromosome 7.
Cyclin-dependent kinase 5 is a protein, and more specifically an enzyme, that is encoded by the Cdk5 gene. It was discovered 15 years ago, and it is saliently expressed in post-mitotic central nervous system neurons (CNS). The molecule belongs to the cyclin-dependent kinase family. Kinases are enzymes that catalyze reactions of phosphorylation. This process allows the substrate to gain a phosphate group donated by an organic compound known as ATP. Phosphorylations are of vital importance during glycolysis, therefore, making kinases an essential part of the cell due to their role in the metabolism, cell signaling, and many other processes. == Structure == Cdk5 is a proline-directed serine/threonine kinase, which was first identified as a CDK family member due to its similar structure to CDC2/CDK1 in humans, a protein that plays a crucial role in the regulation of the cell cycle. The gene Cdk5 contains 12 exons in a region that contains around 5000 nucleotides (5kb), as it was determined by Ohshima after cloning the Cdk5 gene that belonged to a mouse. Cdk5 has 292 amino acids and presents both α-helix and β strand structures. Even though Cdk5 has a similar structure to other cyclin-dependent kinases, its activators are highly specific (CDK5R1 and CDK5R2). Some investigations have reported that the active states of protein kinases structurally differ from each other in order to preserve the geometry of its machinery so that catalytic output works properly.
CDK5, also known as Cell division protein kinase 5, Cyclin-dependent-like kinase 5, Serine/threonine-protein kinase PSSALRE, and Tau protein kinase II catalytic subunit, is a proline-directed serine/threonine-protein kinase that plays a crucial role in neuronal cell cycle arrest and differentiation. It may also be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry. CDK5 interacts with D1 and D3-type G1 cyclins and phosphorylates a wide range of substrates including SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1, SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16, RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53, HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH, and NEFM. Through these phosphorylation events, CDK5 regulates various neuronal developmental and physiological processes, including neuronal survival, migration, and differentiation; axonal and neurite growth; synaptogenesis; oligodendrocyte differentiation; synaptic plasticity; and neurotransmission. CDK5 negatively regulates the CACNA1B/CAV2.2-mediated Ca(2+) release probability at hippocampal neuronal soma and synaptic terminals. CDK5 is activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), particularly in postmitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. It phosphorylates many downstream substrates, including Rho and Ras family small GTPases (e.g. PAK1, RAC1, RHOA, CDC42) and microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. CDK5 also phosphorylates exocytosis-associated proteins, such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1, as well as endocytosis-associated proteins, such as DNM1, AMPH, and SYNJ1, at synaptic terminals. In the mature central nervous system (CNS), CDK5 regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity, including synaptic vesicle exocytosis, vesicle fusion with the presynaptic membrane, and endocytosis. CDK5 promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3 and negatively regulating JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to genotoxic and oxidative stresses enhances its stabilization by preventing ubiquitin ligase-mediated proteasomal degradation, and induces transactivation of p53/TP53 target genes, thus regulating apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by preventing calpain-mediated proteolysis, producing p25/CDK5R1, and avoiding ubiquitin ligase-mediated proteasomal degradation. During aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits cell-cycle activity and double-strand DNA breaks that precede neuronal death by deregulating HDAC1. DNA damage-triggered phosphorylation of huntingtin/HTT in nuclei of neurons protects neurons against polyglutamine expansion, as well as DNA damage-mediated toxicity. Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. CDK5 is a negative regulator of the Wnt/beta-catenin signaling pathway. It is an activator of the GAIT (IFN-gamma-activated inhibitor of translation) pathway, which suppresses expression of a post-transcriptional regulon of proinflammatory genes in myeloid cells; CDK5 phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in an IFN-gamma-dependent manner, the initial event in assembly of the GAIT complex. Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5 in response to osmotic stress mediates its rapid nuclear localization. MEF2 is inactivated by phosphorylation in the nucleus in response to neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-endodeoxyribonuclease is repressed by phosphorylation, resulting in accumulation of DNA damage and contributing to neuronal death. NOS3 phosphorylation downregulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin-dependent degradation, and thus leads to cytoskeletal reorganization. CDK5 may regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. It is involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: it phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-BMAL1 heterodimer in association with altered stability and subcellular distribution. CDK5 forms a heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1 (p25) and a macromolecular complex composed of at least CDK5, CDK5R1 (p35), and CDK5RAP1 or CDK5RAP2 or CDK5RAP3. Only the heterodimer shows kinase activity. Under neurotoxic stress and neuronal injury conditions, p35 is cleaved by calpain to generate p25, which hyperactivates CDK5; CDK5 then becomes functionally disabled and often toxic. CDK5 is found in a trimolecular complex with CABLES1 and ABL1. It interacts with CABLES1 and CABLES2. It also interacts with AATK and GSTP1. CDK5 binds to HDAC1 when in complex with p25. Interaction with myristoylation p35 promotes CDK5 association with membranes. Both isoforms 1 and 2 interact with beta-catenin/CTNNB1. CDK5 interacts with delta-catenin/CTNND2 and APEX1. It interacts with P53/TP53 in neurons. CDK5 interacts with EPHA4; it may mediate the activation of NGEF by EPHA4. It interacts with PTK2/FAK1. The complex p35/CDK5 interacts with CLOCK. CDK5 interacts with HTR6.
CDK5 is also known as LIS7, PSSALRE.
