CDK5_RAT - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: CDK5_RAT
• UniProt AC: Q03114
• Protein Name: Cyclin-dependent-like kinase 5
• Gene Name: Cdk5
• Organism: Rattus norvegicus (Rat).
• Sequence Length: 292
• Subcellular Localization: Cytoplasm. Cell membrane; Peripheral membrane protein. Perikaryon. Cell projection, lamellipodium. Cell projection, growth cone. Nucleus. Cell junction, synapse, postsynaptic cell membrane, postsynaptic density. In axonal growth cone with extension t
• 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 (By similarity)..
• Protein Sequence: MQKYEKLEKIGEGTYGTVFKAKNRETHEIVALKRVRLDDDDEGVPSSALREICLLKELKHKNIVRLHDVLHSDKKLTLVFEFCDQDLKKYFDSCNGDLDPEIVKSLLFQLLKGLGFCHSRNVLHRDLKPQNLLINRNGELKLADFGLARAFGIPVRCYSAEVVTLWYRPPDVLFGAKLYSTSIDMWSAGCIFAELANAGRPLFPGNDVDDQLKRIFRLLGTPTEEQWPAMTKLPDYKPYPMYPATTSLVNVVPKLNATGRDLLQNLLKCNPVQRISAEEALQHPYFSDFCPP

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
14	Phosphorylation	LEKIGEGTYGTVFKA HHHCCCCCCCEEEEE	17.93	28432305
15	Phosphorylation	EKIGEGTYGTVFKAK HHCCCCCCCEEEEEC	22.96	25403869
17	Phosphorylation	IGEGTYGTVFKAKNR CCCCCCCEEEEECCC	16.62	28432305
56	Acetylation	LREICLLKELKHKNI HHHHHHHHHHCCCCE	48.31	-
72	Phosphorylation	RLHDVLHSDKKLTLV EHHHHHCCCCCEEEE	47.14	-
128	Ubiquitination	NVLHRDLKPQNLLIN CCCCCCCCHHCEEEC	49.17	-
141	Ubiquitination	INRNGELKLADFGLA ECCCCCEEEHHHHHH	37.01	-
159	Phosphorylation	GIPVRCYSAEVVTLW CCCEEEEEEEEEEEE	22.91	-
232	Ubiquitination	EQWPAMTKLPDYKPY HHCCCCCCCCCCCCC	44.96	-
237	Ubiquitination	MTKLPDYKPYPMYPA CCCCCCCCCCCCCCC	45.51	-
268	Ubiquitination	DLLQNLLKCNPVQRI HHHHHHHCCCCCCCC	34.82	-
285	Phosphorylation	EEALQHPYFSDFCPP HHHHCCCCHHCCCCC	17.37	-

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	FYN	Q62844	Uniprot
15	Y	Phosphorylation	Kinase	ABL1	-	Uniprot
15	Y	Phosphorylation	Kinase	EPHA4	-	Uniprot
159	S	Phosphorylation	Kinase	CSNK1D	Q06486	GPS

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_RAT !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
PRKN_RAT	Park2	physical	17327227
SYNJ1_RAT	Synj1	physical	14704270
DYN1_RAT	Dnm1	physical	14704270
MPIP1_RAT	Cdc25a	physical	22899714
MPIP2_RAT	Cdc25b	physical	22899714

Drug and Disease Associations

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