CDK5_MOUSE - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: CDK5_MOUSE
• UniProt AC: P49615
• Protein Name: Cyclin-dependent-like kinase 5
• Gene Name: Cdk5
• Organism: Mus musculus (Mouse).
• Sequence Length: 292
• Subcellular Localization: Nucleus. Cytoplasm . Cell membrane; Peripheral membrane protein. Perikaryon. Cell projection, lamellipodium . Cell projection, growth cone . Cell junction, synapse, postsynaptic cell membrane, postsynaptic density. In axonal growth cone with extensio
• Protein Description: 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..
• Protein Sequence: MQKYEKLEKIGEGTYGTVFKAKNRETHEIVALKRVRLDDDDEGVPSSALREICLLKELKHKNIVRLHDVLHSDKKLTLVFEFCDQDLKKYFDSCNGDLDPEIVKSFLFQLLKGLGFCHSRNVLHRDLKPQNLLINRNGELKLADFGLARAFGIPVRCYSAEVVTLWYRPPDVLFGAKLYSTSIDMWSAGCIFAELANAGRPLFPGNDVDDQLKRIFRLLGTPTEEQWPAMTKLPDYKPYPMYPATTSLVNVVPKLNATGRDLLQNLLKCNPVQRISAEEALQHPYFSDFCPP

Overview of Protein Modification Sites with Functional and Structural Information

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
4	Phosphorylation	----MQKYEKLEKIG ----CCHHHHHHHCC	11.04	26824392
9	Ubiquitination	QKYEKLEKIGEGTYG CHHHHHHHCCCCCCC	67.46	22790023
14	Phosphorylation	LEKIGEGTYGTVFKA HHHCCCCCCCEEEEE	17.93	22499769
15	Phosphorylation	EKIGEGTYGTVFKAK HHCCCCCCCEEEEEC	22.96	22322096
17	Phosphorylation	IGEGTYGTVFKAKNR CCCCCCCEEEEECCC	16.62	22499769
56	Acetylation	LREICLLKELKHKNI HHHHHHHHHHCCCCE	48.31	23806337
56	Ubiquitination	LREICLLKELKHKNI HHHHHHHHHHCCCCE	48.31	-
56	Malonylation	LREICLLKELKHKNI HHHHHHHHHHCCCCE	48.31	26320211
72	Phosphorylation	RLHDVLHSDKKLTLV EHHHHHCCCCCEEEE	47.14	-
128	Ubiquitination	NVLHRDLKPQNLLIN CCCCCCCCHHCEEEC	49.17	22790023
141	Ubiquitination	INRNGELKLADFGLA ECCCCCEEEHHHHHH	37.01	22790023
159	Phosphorylation	GIPVRCYSAEVVTLW CCCEEEEEEEEEEEE	22.91	19542233
237	Ubiquitination	MTKLPDYKPYPMYPA CCCCCCCCCCCCCCC	45.51	22790023
254	Ubiquitination	SLVNVVPKLNATGRD HHHHHHHCCCCCCHH	42.64	22790023
268	Ubiquitination	DLLQNLLKCNPVQRI HHHHHHHCCCCCCCC	34.82	-
287	Phosphorylation	ALQHPYFSDFCPP-- HHCCCCHHCCCCC--	24.76	25338131

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
15	Y	Phosphorylation	Kinase	ABL	P00520	PSP
15	Y	Phosphorylation	Kinase	EPHA4	Q03137	Uniprot
15	Y	Phosphorylation	Kinase	FYN	P39688	Uniprot
15	Y	Phosphorylation	Kinase	ERK1	P27361	PSP

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
14	T	Phosphorylation	By contrast, phosphorylation at Thr-14 inhibits activity (By similarity).	-
159	S	Phosphorylation	Phosphorylation at Ser-159 is essential for maximal catalytic activity.	-
159	S	Phosphorylation	Phosphorylation on Tyr-15 by ABL1 and FYN, and on Ser-159 by casein kinase 1 promotes kinase activity.	-

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Oops, there are no SNP-PTM records of CDK5_MOUSE !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
CD5R1_MOUSE	Cdk5r1	physical	12496365
PURA_MOUSE	Pura	physical	12972605
H10_MOUSE	H1f0	physical	11343650
NFH_MOUSE	Nefh	physical	11343650
CHIP_MOUSE	Stub1	physical	26206088
H11_HUMAN	HIST1H1A	physical	26206088

Drug and Disease Associations

• Kegg Drug
• DrugBank
• There are no disease associations of PTM sites.

Related Literatures of Post-Translational Modification

Phosphorylation

"Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosinephosphorylation, kinase upregulation, and neurite outgrowth.";
Zukerberg L.R., Patrick G.N., Nikolic M., Humbert S., Wu C.-L.,Lanier L.M., Gertler F.B., Vidal M., Van Etten R.A., Tsai L.-H.;
Neuron 26:633-646(2000).
Cited for: IDENTIFICATION IN A TRIMOLECULAR COMPLEX WITH CABLES1 AND ABL1,INTERACTION WITH CABLES1, PHOSPHORYLATION AT TYR-15, AND MUTAGENESISOF TYR-15.
PubMed: 10896159