Function |
Proline-directed serine/threonine-protein kinaseessential for neuronal cell cycle arrest and differentiation andmay be involved in apoptotic cell death in neuronal diseases bytriggering 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 severalneuronal development and physiological processes includingneuronal survival, migration and differentiation, axonal andneurite growth, synaptogenesis, oligodendrocytes differentiation,synaptic plasticity and neurotransmission, by phosphorylating keyproteins. Activated by interaction with CDK5R1 (p35) and ATP6V0D1(p39), especially in post-mitotic neurons, and promotes CDK5R1(p35) expression in an autostimulation loop. Phosphorylates manydownstream 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 toregulate neurite growth and/or spine morphogenesis. Phosphorylatesalso exocytosis associated proteins such as MCAM/MUC18, SEPT5,SYN1, and PCTAIRE 1/CDK16 as well as endocytosis associatedproteins such as DNM1, AMPH and SYNJ1 at synaptic terminals. Inthe mature central nervous system (CNS), regulatesneurotransmitter movements by phosphorylating substratesassociated with neurotransmitter release and synapse plasticity;synaptic vesicle exocytosis, vesicles fusion with the presynapticmembrane, and endocytosis. Promotes cell survival by activatinganti-apoptotic proteins BCL2 and STAT3, and negatively regulatingof JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in responseto genotoxic and oxidative stresses enhances its stabilization bypreventing ubiquitin ligase-mediated proteasomal degradation, andinduces transactivation of p53/TP53 target genes, thus regulatingapoptosis. Phosphorylation of p35/CDK5R1 enhances itsstabilization by preventing calpain-mediated proteolysis producingp25/CDK5R1 and avoiding ubiquitin ligase-mediated proteasomaldegradation. During aberrant cell-cycle activity and DNA damage,p25/CDK5 activity elicites cell-cycle activity and double-strandDNA breaks that precedes neuronal death by deregulating HDAC1. DNAdamage triggered phosphorylation of huntingtin/HTT in nuclei ofneurons protects neurons against polyglutamine expansion as wellas DNA damage mediated toxicity. Phosphorylation of PXN reducesits interaction with PTK2/FAK1 in matrix-cell focal adhesions(MCFA) during oligodendrocytes (OLs) differentiation. Negativeregulator of Wnt/beta-catenin signaling pathway. Activator of theGAIT (IFN-gamma-activated inhibitor of translation) pathway, whichsuppresses expression of a post-transcriptional regulon ofproinflammatory genes in myeloid cells; phosphorylates the linkerdomain of glutamyl-prolyl tRNA synthetase (EPRS) in a IFN-gamma-dependent manner, the initial event in assembly of the GAITcomplex. Phosphorylation of SH3GLB1 is required for autophagyinduction in starved neurons. Phosphorylation of TONEBP/NFAT5 inresponse to osmotic stress mediates its rapid nuclearlocalization. MEF2 is inactivated by phosphorylation in nucleus inresponse to neurotoxin, thus leading to neuronal apoptosis. APEX1AP-endodeoxyribonuclease is repressed by phosphorylation,resulting in accumulation of DNA damage and contributing toneuronal death. NOS3 phosphorylation down regulates NOS3-derivednitrite (NO) levels. SRC phosphorylation mediates its ubiquitin-dependent degradation and thus leads to cytoskeletalreorganization. May regulate endothelial cell migration andangiogenesis via the modulation of lamellipodia formation.Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. Back to Top |