DAPK1

DAPK1 is calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. DAPK1 regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. DAPK1 phosphorylates PIN1 resulting in inhibition of its catalytic activity, nuclear localization, and cellular function. DAPK1 phosphorylates TPM1, enhancing stress fiber formation in endothelial cells. Phosphorylates STX1A and significantly decreases its binding to STXBP1. DAPK1 phosphorylates PRKD1 and regulates JNK signaling by binding and activating PRKD1 under oxidative stress. DAPK1 phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. DAPK1 phosphorylates TSC2, disrupting the TSC1-TSC2 complex and stimulating mTORC1 activity in a growth factor-dependent pathway. DAPK1 phosphorylates RPS6, MYL9 and DAPK3. DAPK1 acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex and it phosphorylates GRINB at Ser-1303 inducing injurious Ca2+ influx through NMDA receptor channels, resulting in an irreversible neuronal death.

DAPK1 Related Areas

Enzyme>>Protein Kinase>>Intracellular Kinase>>DAPK1

Signal Transduction>>Protein Kinase>>Intracellular Kinase>>DAPK1

DAPK1 Alternative Names

DAPK1, DAPK, DKFZp781I035 [Homo sapiens]

Dapk1, 2310039H24Rik, 2810425C21Rik, AI642003, D13Ucla1, DAP-Kinase [Mus musculus]

Summaries for DAPK1

Entrez Gene summary for DAPK1:

Death-associated protein kinase 1 is a positive mediator of gamma-interferon induced programmed cell death. DAPK1 encodes a structurally unique 160-kD calmodulin dependent serine-threonine kinase that carries 8 ankyrin repeats and 2 putative P-loop consensus sites. DAPK1 is a tumor suppressor candidate. [provided by RefSeq, Jul 2008]

Wikipedia summary for DAPK1:

Death-associated protein kinase 1 is an enzyme that in humans is encoded by the DAPK1 gene.
In melanocytic cells DAPK1 gene expression may be regulated by MITF.

Human DAPK1 Protein General Information

 

• Protein names: Death-associated protein kinase 1, Short name=DAP kinase 1
• Sequence length: 1430 AA.
• Domain: The autoinhibitory domain sterically blocks the substrate peptide-binding site by making both hydrophobic and electrostatic contacts with the kinase core.
• Catalytic activity: ATP + a protein = ADP + a phosphoprotein.
• Cofactor: Magnesium.
• Enzyme regulation: DAPK1 is activated by Ca2+/calmodulin. DAPK1 is regulated by a locking mechanism, involving autophosphorylation at Ser-308 and calmodulin binding. In the inactive state, Ser-308 is phosphorylated. Activation involves its dephosphorylation and a release-of-autoinhibition mechanism where binding of calmodulin induces a conformational change that relieves the steric block of the active site by the autoinhibitory domain. Activity is modulated by UNC5B and NTN1. UNC5B activates it by inhibiting the phosphorylation at Ser-308, whereas NTN1 inhibits UNC5B-mediated activation of DAPK1. Endoplasmic-stress activates by causing Ser-308 dephosphorylation.
• Sequence similarities: DAPK1 belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. DAP kinase subfamily. DAPK1 contains 10 ANK repeats. DAPK1 contains 1 death domain. DAPK1 contains 1 protein kinase domain.
• Post-translational modification: DAPK1 is ubiquitinated by the BCR(KLHL20) E3 ubiquitin ligase complex, leading to its degradation by the proteasome.
  Removal of the C-terminal tail of isoform 2 (correponding to amino acids 296-337 of isoform 2) by proteolytic cleavage stimulates maximally its membrane-blebbing function.
  In response to mitogenic stimulation (PMA or EGF), phosphorylated at Ser-289; phosphorylation suppresses DAPK1 pro-apoptotic function. Autophosphorylation at Ser-308 inhibits its catalytic activity. Phosphorylation at Ser-734 by MAPK1 increases its catalytic activity and promotes cytoplasmic retention of MAPK1. Endoplasmic-stress can cause dephosphorylation at Ser-308.
• Subunit structure: DAPK1 interacts with KLHL20. DAPK1 interacts (via death domain) with MAPK1 and MAPK3. DAPK1 interacts with MAP1B (via N-terminus). DAPK1 interacts (via death domain) with UNC5B (via death domain). It interacts with PRKD1 in an oxidative stress-regulated manner. DAPK1 interacts with PIN1, PDCD6, BECN1, GRINB, TSC2 and STX1A. Interacts (via kinase domain) with DAPK3 (via kinase domain).
• Subcellular location: Isoform 1: Cytoplasm. Cytoplasm › cytoskeleton. Note: Colocalizes with MAP1B in the microtubules and cortical actin fibers.
  Isoform 2: Cytoplasm. Cytoplasm › cytoskeleton
• Tissue specificity: Isoform 2 is expressed in normal intestinal tissue as well as in colorectal carcinomas.
• Induction: Up-regulated following treatment with IFNG/IFN-gamma.
• Sequence caution: The sequence AAP35581.1 differs from that shown. Reason: Contaminating sequence. Sequence of unknown origin in the C-terminal part.
  The sequence CAA53712.1 differs from that shown. Reason: Frameshift at positions 462 and 464.

General information above from UniProt

Function for DAPK1 Protein

UniProtKB:

DAPK1 is calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. DAPK1 regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. DAPK1 phosphorylates PIN1 resulting in inhibition of its catalytic activity, nuclear localization, and cellular function. DAPK1 phosphorylates TPM1, enhancing stress fiber formation in endothelial cells. Phosphorylates STX1A and significantly decreases its binding to STXBP1. DAPK1 phosphorylates PRKD1 and regulates JNK signaling by binding and activating PRKD1 under oxidative stress. DAPK1 phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. DAPK1 phosphorylates TSC2, disrupting the TSC1-TSC2 complex and stimulating mTORC1 activity in a growth factor-dependent pathway. DAPK1 phosphorylates RPS6, MYL9 and DAPK3. DAPK1 acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex and it phosphorylates GRINB at Ser-1303 inducing injurious Ca2+ influx through NMDA receptor channels, resulting in an irreversible neuronal death.

Genatlas:

• DAPK1 has adhesion inhibitory effect, inducing death coupling the control of apoptosis to metastasis
• DAPK1 is calcium/calmodulin serine/threonine kinase, which positively mediates programmed cell death in a variety of systems
• DAPK1 is involved in Fas-induced extrinsic apoptosis in lymphoid cells
• DAPK1 phosphorylates BECN1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of BECN1 from BCL2L1 and the induction of autophagy
• DAPK1 phosphorylates tropomyosin-1 in response to ERK activation by hydrogen peroxide (H(2)O(2), and regulates the formation of stress fibers in response to oxidative stress
• modulation of DAPK1 activities is critical for regulation of apoptosis and cellular homeostasis
• DAPK1 phosphorylates GRIN2B and in turn enhancing the NR1/NR2B receptor channel conductance
• DAPK1 promotes cell death partly through its effect on regulating actin cytoskeletons
• DAPK1 is molecular link of DAPK to tau phosphorylation, an event associated with Alzheimer disease pathology
• DAPK1 inhibits the ability of PIN1 to induce centrosome amplification and cell transformation
• DAPK1 is calmodulin-dependent protein kinases that are regulated by oligomerization, calmodulin binding, and autophosphorylation