Function
Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry. Interacts with D1 and D3-type G1 cyclins. Phosphorylates 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. Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), especially in post-mitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. Phosphorylates many downstream substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1, RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. Phosphorylates also 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), regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity; synaptic vesicle exocytosis, vesicles fusion with the presynaptic membrane, and endocytosis. Promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3, and negatively regulating of 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 precedes 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. Negative regulator of Wnt/beta-catenin signaling pathway. 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; phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in a 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 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 down regulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. May regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. 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: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer in association with altered stability and subcellular distribution.
Biological Process
Axon extension Source: UniProtKB
Axonogenesis Source: GO_Central
Behavioral response to cocaine Source: Ensembl
Calcium ion import Source: Ensembl
Cell division Source: UniProtKB-KW
Cell-matrix adhesion Source: Ensembl
Cellular response to amyloid-beta Source: ARUK-UCL
Central nervous system neuron development Source: Ensembl
Cerebellar cortex formation Source: Ensembl
Chemical synaptic transmission Source: UniProtKB
Corpus callosum development Source: Ensembl
Cortical actin cytoskeleton organization Source: Ensembl
Dendrite morphogenesis Source: Ensembl
Excitatory postsynaptic potential Source: Ensembl
Hippocampus development Source: Ensembl
Histone phosphorylation Source: Ensembl
Intracellular protein transport Source: Ensembl
Layer formation in cerebral cortex Source: Ensembl
Microtubule cytoskeleton organization Source: ARUK-UCL
Mitochondrion organization Source: Ensembl
Motor neuron axon guidance Source: Ensembl
Negative regulation of axon extension Source: Ensembl
Negative regulation of cell cycle Source: Ensembl
Negative regulation of neuron death Source: ParkinsonsUK-UCL
Negative regulation of protein export from nucleus Source: Ensembl
Negative regulation of protein ubiquitination Source: Ensembl
Negative regulation of proteolysis Source: ParkinsonsUK-UCL
Negative regulation of synaptic plasticity Source: Ensembl
Negative regulation of transcription, DNA-templated Source: DFLAT
Neuron apoptotic process Source: GO_Central
Neuron differentiation Source: UniProtKB
Neuron migration Source: UniProtKB
Neuron projection development Source: UniProtKB
Nucleocytoplasmic transport Source: Ensembl
Oligodendrocyte differentiation Source: UniProtKB
Peptidyl-serine phosphorylation Source: UniProtKB
Peptidyl-threonine phosphorylation Source: ARUK-UCL
Phosphorylation Source: DFLAT
Positive regulation of actin cytoskeleton reorganization Source: UniProtKB
Positive regulation of calcium ion-dependent exocytosis Source: Ensembl
Positive regulation of glial cell apoptotic process Source: Ensembl
Positive regulation of neuron apoptotic process Source: UniProtKB
Positive regulation of protein binding Source: Ensembl
Positive regulation of protein kinase activity Source: Ensembl
Positive regulation of protein targeting to membrane Source: Ensembl
Positive regulation of voltage-gated calcium channel activity Source: Ensembl
Protein autophosphorylation Source: Ensembl
Protein localization to synapse Source: Ensembl
Protein phosphorylation Source: GO_Central
Receptor catabolic process Source: Ensembl
Receptor clustering Source: Ensembl
Regulation of apoptotic process Source: UniProtKB
Regulation of cell cycle arrest Source: UniProtKB
Regulation of cell migration Source: Ensembl
Regulation of dendritic spine morphogenesis Source: UniProtKB
Regulation of macroautophagy Source: ParkinsonsUK-UCL
Regulation of protein localization to plasma membrane Source: ARUK-UCL
Regulation of signal transduction by p53 class mediator Source: Reactome
Regulation of synaptic plasticity Source: UniProtKB
Regulation of synaptic transmission, glutamatergic Source: ARUK-UCL
Regulation of synaptic vesicle recycling Source: ParkinsonsUK-UCL
Regulation of transcription involved in G1/S transition of mitotic cell cycle Source: GO_Central
Response to wounding Source: Ensembl
Rhythmic process Source: UniProtKB-KW
Schwann cell development Source: Ensembl
Sensory perception of pain Source: Ensembl
Serine phosphorylation of STAT protein Source: Ensembl
Skeletal muscle tissue development Source: Ensembl
Synapse assembly Source: UniProtKB
Synapse pruning Source: Ensembl
Synaptic transmission, dopaminergic Source: Ensembl
Synaptic transmission, glutamatergic Source: Ensembl
Synaptic vesicle endocytosis Source: UniProtKB
Synaptic vesicle exocytosis Source: UniProtKB
Synaptic vesicle transport Source: GO_Central
Visual learning Source: Ensembl
Cellular Location
Isoform 1: Cell membrane; Cytoplasm; Perikaryon; Lamellipodium; Growth cone; Postsynaptic density. In axonal growth cone with extension to the peripheral lamellipodia (By similarity). Under neurotoxic stress and neuronal injury conditions, CDK5R (p35) is cleaved by calpain to generate CDK5R1 (p25) in response to increased intracellular calcium. The elevated level of p25, when in complex with CDK5, leads to its subcellular misallocation as well as its hyperactivation. Colocalizes with CTNND2 in the cell body of neuronal cells, and with CTNNB1 in the cell-cell contacts and plasma membrane of undifferentiated and differentiated neuroblastoma cells. Reversibly attached to the plasma membrane in an inactive form when complexed to dephosphorylated p35 or CDK5R2 (p39), p35 phosphorylation releases this attachment and activates CDK5.
Isoform 2: Nucleus
Involvement in disease
Lissencephaly 7, with cerebellar hypoplasia (LIS7): A form of lissencephaly, a disorder of cortical development characterized by agyria or pachygyria and disorganization of the clear neuronal lamination of normal six-layered cortex. LIS7 patients manifest lack of psychomotor development, facial dysmorphism, arthrogryposis, and early-onset intractable seizures resulting in death in infancy.
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