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 neurotr (updated: Oct. 10, 2018)

Protein identification was indicated in the following studies:

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

Publication	Identification ¹	Uniprot mapping ²	Not mapped / Obsolete	TrEMBL	Swiss-Prot
Goodman (2013)	2289 (gene list)	2278	53	20599	2269
Lange (2014)	1234	1234	7	28	1224
Hegedus (2015)	2638	2622	0	235	2387
Wilson (2016)	1658	1528	170	291	1068
d'Alessandro (2017)	1826	1817	2	0	1815
Bryk (2017)	2090	2060	10	108	1942
Chu (2018)	1853	1804	55	362	1387

¹ as available in the article and/or in supplementary material
² uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Protein sequence (FASTA)

Protein coevolution profile (FreeContact)

Multiple Sequence Alignment (Muscle)

This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.

Total structural coverage: 100%

Model score: 100

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Variant	Description
	dbSNP:rs35186917

Biological Process

Axon extension

Axonogenesis

Behavioral response to cocaine

Calcium ion import

Cell cycle

Cell division

Cell-matrix adhesion

Cellular response to amyloid-beta

Central nervous system neuron development

Cerebellar cortex formation

Chemical synaptic transmission

Corpus callosum development

Cortical actin cytoskeleton organization

Dendrite morphogenesis

Excitatory postsynaptic potential

Hippocampus development

Histone phosphorylation

Intracellular protein transport

Layer formation in cerebral cortex

Microtubule cytoskeleton organization

Mitochondrion organization

Motor neuron axon guidance

Negative regulation of axon extension

Negative regulation of cell cycle

Negative regulation of neuron death

Negative regulation of protein export from nucleus

Negative regulation of protein ubiquitination

Negative regulation of proteolysis

Negative regulation of synaptic plasticity

Negative regulation of transcription, DNA-templated

Neuron apoptotic process

Neuron differentiation

Neuron migration

Neuron projection development

Nucleocytoplasmic transport

Oligodendrocyte differentiation

Peptidyl-serine phosphorylation

Peptidyl-threonine phosphorylation

Phosphorylation

Positive regulation of actin cytoskeleton reorganization

Positive regulation of calcium ion-dependent exocytosis

Positive regulation of glial cell apoptotic process

Positive regulation of neuron apoptotic process

Positive regulation of protein binding

Positive regulation of protein kinase activity

Positive regulation of protein targeting to membrane

Positive regulation of voltage-gated calcium channel activity

Protein autophosphorylation

Protein localization to synapse

Protein phosphorylation

Receptor catabolic process

Receptor clustering

Regulation of apoptotic process

Regulation of cell cycle arrest

Regulation of cell migration

Regulation of dendritic spine morphogenesis

Regulation of macroautophagy

Regulation of protein localization to plasma membrane

Regulation of signal transduction by p53 class mediator

Regulation of synaptic plasticity

Regulation of synaptic transmission, glutamatergic

Regulation of synaptic vesicle recycling

Regulation of transcription involved in G1/S transition of mitotic cell cycle

Response to wounding

Rhythmic process

Schwann cell development

Sensory perception of pain

Serine phosphorylation of STAT protein

Skeletal muscle tissue development

Synapse assembly

Synapse pruning

Synaptic transmission, dopaminergic

Synaptic transmission, glutamatergic

Synaptic vesicle endocytosis

Synaptic vesicle exocytosis

Synaptic vesicle transport

Visual learning

Cellular Component

Axon

Cell junction

Cytoplasm

Cytosol

Dendrite

Filopodium

Glutamatergic synapse

Growth cone

Lamellipodium

Membrane

Microtubule

Neuromuscular junction

Neuron projection

Neuronal cell body

Nucleoplasm

Nucleus

Obsolete cell

Perikaryon

Plasma membrane

Postsynaptic density

Presynapse

Protein kinase 5 complex

Schaffer collateral - CA1 synapse

Molecular Function

Acetylcholine receptor activator activity

ATP binding

Cyclin-dependent protein serine/threonine kinase activity

Ephrin receptor binding

ErbB-2 class receptor binding

ErbB-3 class receptor binding

Hsp90 protein binding

Kinase activity

P53 binding

Protein kinase activity

Protein kinase binding

Protein serine kinase activity

Protein serine/threonine kinase activity

Protein threonine kinase activity

Tau protein binding

Tau-protein kinase activity

Voltage-gated calcium channel activity involved in positive regulation of presynaptic cytosolic calcium levels

The reference OMIM entry for this protein is 123831

Cyclin-dependent kinase 5; cdk5
Cell division kinase 5
Pssalre

DESCRIPTION

CDK5, a member of the cyclin-dependent kinase family, is prominently expressed in postmitotic central nervous system (CNS) neurons (summary by Magen et al., 2015).

CLONING

The p34(CDC2) protein kinase (116940) regulates important transitions in the eukaryotic cell cycle. Using RT-PCR of HeLa cell mRNA with degenerate primers corresponding to conserved regions of CDC2, Meyerson et al. (1992) identified cDNAs encoding 7 novel human protein kinases. They designated one of these proteins PSSALRE, following the accepted practice of naming cdc2-related kinases based on the amino acid sequence of the region corresponding to the conserved PSTAIRE motif of CDC2. The predicted 291-amino acid PSSALRE protein shares 57% identity with CDC2. The in vitro transcription/translation product has an apparent molecular weight of 31 kD by SDS-PAGE. Northern blot analysis detected PSSALRE expression in all human tissues and cell lines tested.

GENE FUNCTION

Cyclin-dependent kinase-5 is predominantly expressed in neurons where it phosphorylates both high molecular weight neurofilaments (NEFH; 162230) and microtubule-associated protein tau (157140) (Ohshima et al., 1995). CDK5 is required for proper development of the mammalian CNS. To be activated, CDK5 must associate with its regulatory subunit, p35 (CDK5R1; 603460). Patrick et al. (1999) showed that p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer disease (104300). This accumulation correlated with an increase in CDK5 kinase activity. Unlike p35, p25 was not readily degraded, and binding of p25 to CDK5 constitutively activated CDK5, changed its cellular location, and altered its substrate specificity. In vivo, the p25/CDK5 complex hyperphosphorylated tau, which reduced tau's ability to associate with microtubules. Moreover, expression of the p25/CDK5 complex in cultured primary neurons induced cytoskeletal disruption, morphologic degeneration, and apoptosis. Patrick et al. (1999) concluded that cleavage of p35, followed by accumulation of p25, may be involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative diseases. Bibb et al. (1999) demonstrated that CDK5 can phosphorylate DARPP32 (604399) at threonine-75, converting it into an inhibitor of PKA (see 176911). Cocaine enhances dopamine-mediated neurotransmission by blocking dopamine reuptake at axon terminals. Most dopamine-containing nerve terminals innervate medium spiny neurons in the striatum of the brain. Cocaine addiction is thought to stem, in part, from neural adaptations that act to maintain equilibrium by countering the effects of repeated drug administration. Chronic exposure to cocaine upregulates several transcription factors that alter gene expression and which could mediate such compensatory neural and behavioral changes. One such transcription factor is delta-FosB (164772), a protein that persists in striatum long after the end of cocaine exposure. Bibb et al. (2001) identified Cdk5 as a downstream target of delta-FosB by use of DNA array analysis of striatal material from inducible transgenic mice. Overexpression of delta-FosB, or chronic cocaine administration, raised levels of Cdk5 mRNA, protein, and activity in the striatum. Moreover, injection of Cdk5 inhibitors into the striatum potentiated behavioral effects of repeated cocaine administration. Bibb et al. (2001) concluded that changes in Cdk5 levels mediat ... More on the omim web site

Subscribe to this protein entry history

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 123831 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).

Cyclin-dependent-like kinase 5 (CDK5)