InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: CDK5

Summary

InnateDB Protein

IDBP-482107.3

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

CDK5

Protein Name

cyclin-dependent kinase 5

Synonyms

PSSALRE;

Species

Homo sapiens

Ensembl Protein

ENSP00000419782

InnateDB Gene

IDBG-48977 (CDK5)

Protein Structure

UniProt Annotation

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. {ECO:0000269PubMed:12393264, ECO:0000269PubMed:12691662, ECO:0000269PubMed:15992363, ECO:0000269PubMed:17009320, ECO:0000269PubMed:17121855, ECO:0000269PubMed:17591690, ECO:0000269PubMed:17611284, ECO:0000269PubMed:17671990, ECO:0000269PubMed:18042622, ECO:0000269PubMed:19081376, ECO:0000269PubMed:19693690, ECO:0000269PubMed:20061803, ECO:0000269PubMed:20213743, ECO:0000269PubMed:20826806, ECO:0000269PubMed:21209322, ECO:0000269PubMed:21220307, ECO:0000269PubMed:21442427, ECO:0000269PubMed:21465480, ECO:0000269PubMed:21499257, ECO:0000269PubMed:24235147, ECO:0000269PubMed:9822744}.

Subcellular Localization

Isoform 1: Cytoplasm. Cell membrane; Peripheral membrane protein. Perikaryon. Cell projection, lamellipodium {ECO:0000250}. Cell projection, growth cone {ECO:0000250}. Cell junction, synapse, postsynaptic cell membrane, postsynaptic density {ECO:0000250}. Note=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. {ECO:0000250}.Isoform 2: Nucleus.

Disease Associations

Tissue Specificity

Isoform 1 is ubiquitously expressed. Accumulates in cortical neurons (at protein level). Isoform 2 has only been detected in testis, skeletal muscle, colon, bone marrow and ovary. {ECO:0000269PubMed:17009320, ECO:0000269PubMed:19693690}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 98 experimentally validated interaction(s) in this database.
They are also associated with 9 interaction(s) predicted by orthology.

Experimentally validated
Total	98 [view]
Protein-Protein	97 [view]
Protein-DNA	1 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	9 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0002039	p53 binding
GO:0004672	protein kinase activity
GO:0004674	protein serine/threonine kinase activity
GO:0004693	cyclin-dependent protein serine/threonine kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0005176	ErbB-2 class receptor binding
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0008092	cytoskeletal protein binding
GO:0016301	kinase activity
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0030549	acetylcholine receptor activator activity
GO:0043125	ErbB-3 class receptor binding
GO:0046875	ephrin receptor binding
GO:0050321	tau-protein kinase activity

Biological Process

GO:0001764	neuron migration
GO:0001963	synaptic transmission, dopaminergic
GO:0006468	protein phosphorylation
GO:0006886	intracellular protein transport
GO:0006887	exocytosis
GO:0006913	nucleocytoplasmic transport
GO:0006915	apoptotic process
GO:0007049	cell cycle
GO:0007160	cell-matrix adhesion
GO:0007268	synaptic transmission
GO:0007409	axonogenesis
GO:0007411	axon guidance
GO:0007416	synapse assembly
GO:0007519	skeletal muscle tissue development
GO:0007596	blood coagulation
GO:0008045	motor neuron axon guidance
GO:0008283	cell proliferation
GO:0008306	associative learning
GO:0008542	visual learning
GO:0009611	response to wounding
GO:0009790	embryo development
GO:0014044	Schwann cell development
GO:0016079	synaptic vesicle exocytosis
GO:0016310	phosphorylation
GO:0016477	cell migration
GO:0018105	peptidyl-serine phosphorylation
GO:0018107	peptidyl-threonine phosphorylation
GO:0019233	sensory perception of pain
GO:0021537	telencephalon development
GO:0021549	cerebellum development
GO:0021695	cerebellar cortex development
GO:0021697	cerebellar cortex formation
GO:0021766	hippocampus development
GO:0021819	layer formation in cerebral cortex
GO:0021954	central nervous system neuron development
GO:0021987	cerebral cortex development
GO:0022038	corpus callosum development
GO:0030182	neuron differentiation
GO:0030334	regulation of cell migration
GO:0030517	negative regulation of axon extension
GO:0030866	cortical actin cytoskeleton organization
GO:0030900	forebrain development
GO:0031175	neuron projection development
GO:0031397	negative regulation of protein ubiquitination
GO:0031914	negative regulation of synaptic plasticity
GO:0032092	positive regulation of protein binding
GO:0032801	receptor catabolic process
GO:0033136	serine phosphorylation of STAT3 protein
GO:0035249	synaptic transmission, glutamatergic
GO:0035418	protein localization to synapse
GO:0042220	response to cocaine
GO:0042981	regulation of apoptotic process
GO:0043113	receptor clustering
GO:0043525	positive regulation of neuron apoptotic process
GO:0045055	regulated secretory pathway
GO:0045786	negative regulation of cell cycle
GO:0045860	positive regulation of protein kinase activity
GO:0045861	negative regulation of proteolysis
GO:0045892	negative regulation of transcription, DNA-templated
GO:0045956	positive regulation of calcium ion-dependent exocytosis
GO:0046777	protein autophosphorylation
GO:0046826	negative regulation of protein export from nucleus
GO:0048148	behavioral response to cocaine
GO:0048167	regulation of synaptic plasticity
GO:0048488	synaptic vesicle endocytosis
GO:0048511	rhythmic process
GO:0048675	axon extension
GO:0048709	oligodendrocyte differentiation
GO:0048812	neuron projection morphogenesis
GO:0048813	dendrite morphogenesis
GO:0051301	cell division
GO:0051402	neuron apoptotic process
GO:0060078	regulation of postsynaptic membrane potential
GO:0060079	regulation of excitatory postsynaptic membrane potential
GO:0061001	regulation of dendritic spine morphogenesis
GO:0070509	calcium ion import
GO:0071156	regulation of cell cycle arrest
GO:0090314	positive regulation of protein targeting to membrane
GO:1901215	negative regulation of neuron death
GO:2000251	positive regulation of actin cytoskeleton reorganization
GO:2000273	positive regulation of receptor activity

Cellular Component

GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005829	cytosol
GO:0005856	cytoskeleton
GO:0014069	postsynaptic density
GO:0016020	membrane
GO:0016533	cyclin-dependent protein kinase 5 holoenzyme complex
GO:0030027	lamellipodium
GO:0030054	cell junction
GO:0030175	filopodium
GO:0030424	axon
GO:0030425	dendrite
GO:0030426	growth cone
GO:0031594	neuromuscular junction
GO:0043025	neuronal cell body
GO:0043204	perikaryon
GO:0045211	postsynaptic membrane

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR011009 Protein kinase-like domain
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF07714

PRINTS

PR00109

PIRSF

SMART

SM00220
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt