UniProt functional annotation for P19525



	UniProt functional annotation for P19525

UniProt code: P19525.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: IFN-induced dsRNA-dependent serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the innate immune response to viral infection (PubMed:18835251, PubMed:19507191, PubMed:19189853, PubMed:21123651, PubMed:21072047, PubMed:22948139, PubMed:23229543, PubMed:22381929). Inhibits viral replication via the integrated stress response (ISR): EIF2S1/eIF-2- alpha phosphorylation in response to viral infection converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, resulting to a shutdown of cellular and viral protein synthesis, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4 (PubMed:19189853, PubMed:21123651, PubMed:22948139, PubMed:23229543). Exerts its antiviral activity on a wide range of DNA and RNA viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) and herpes simplex virus 1 (HHV-1) (PubMed:11836380, PubMed:19189853, PubMed:20171114, PubMed:19840259, PubMed:21710204, PubMed:23115276, PubMed:23399035). Also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation: phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11 (PubMed:11836380, PubMed:22214662, PubMed:19229320). In addition to serine/threonine- protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteosomal degradation (PubMed:20395957). Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding proinflammatory cytokines and IFNs (PubMed:22948139, PubMed:23084476, PubMed:23372823). Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6 (PubMed:10848580, PubMed:15121867, PubMed:15229216). Can act as both a positive and negative regulator of the insulin signaling pathway (ISP) (PubMed:20685959). Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2) (PubMed:20685959). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes (PubMed:22801494). Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin (By similarity). {ECO:0000250|UniProtKB:Q03963, ECO:0000269|PubMed:10848580, ECO:0000269|PubMed:11836380, ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:15229216, ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:19189853, ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:19507191, ECO:0000269|PubMed:19840259, ECO:0000269|PubMed:20171114, ECO:0000269|PubMed:20395957, ECO:0000269|PubMed:20685959, ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:21123651, ECO:0000269|PubMed:21710204, ECO:0000269|PubMed:22214662, ECO:0000269|PubMed:22381929, ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:22948139, ECO:0000269|PubMed:23084476, ECO:0000269|PubMed:23115276, ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:23372823, ECO:0000269|PubMed:23399035, ECO:0000269|PubMed:32197074}.

Catalytic activity: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;

Catalytic activity: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;

Catalytic activity: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2; Evidence={ECO:0000255|PROSITE-ProRule:PRU10027};

Activity regulation: Initially produced in an inactive form and is activated by binding to viral dsRNA, which causes dimerization and autophosphorylation in the activation loop and stimulation of function. ISGylation can activate it in the absence of viral infection. Can also be activated by heparin, proinflammatory stimuli, growth factors, cytokines, oxidative stress and the cellular protein PRKRA. Activity is markedly stimulated by manganese ions. Activation is blocked by the viral components HIV-1 Tat protein and large amounts of HIV-1 trans- activation response (TAR) RNA element as well as by the cellular proteins TARBP2, DUS2L, NPM1, NCK1 and ADAR. Down-regulated by Toscana virus (TOS) and Rift valley fever virus (RVFV) NSS which promote its proteasomal degradation. Inhibited by vaccinia virus protein E3, probably via dsRNA sequestering. {ECO:0000269|PubMed:12882984, ECO:0000269|PubMed:18096616, ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:23325696}.

Subunit: Homodimer. Interacts with STRBP (By similarity). Interacts with DNAJC3. Forms a complex with FANCA, FANCC, FANCG and HSP70. Interacts with ADAR/ADAR1. Interacts with IRS1 (By similarity). The inactive form interacts with NCK1 and GSN. Interacts (via the kinase catalytic domain) with STAT3 (via SH2 domain), TRAF2 (C-terminus), TRAF5 (C-terminus) and TRAF6 (C-terminus). Interacts with MAP2K6, IKBKB/IKKB, NPM1, TARBP2, NLRP1, NLRP3, NLRC4 and AIM2. Interacts (via DRBM 1 domain) with DUS2L (via DRBM domain). Interacts with DHX9 (via N-terminus) and this interaction is dependent upon activation of the kinase. {ECO:0000250|UniProtKB:Q03963, ECO:0000269|PubMed:10390359, ECO:0000269|PubMed:10848580, ECO:0000269|PubMed:11438532, ECO:0000269|PubMed:12882984, ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:15229216, ECO:0000269|PubMed:15299030, ECO:0000269|PubMed:16179258, ECO:0000269|PubMed:17079286, ECO:0000269|PubMed:18096616, ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:23084476, ECO:0000269|PubMed:25740987, ECO:0000269|PubMed:8576172, ECO:0000269|PubMed:9079663, ECO:0000269|PubMed:9143277, ECO:0000269|PubMed:9781815}.

Subunit: (Microbial infection) Interacts with human herpes simplex virus 1 (HHV-1) protein US11 in an RNA-dependent manner. {ECO:0000269|PubMed:11836380}.

Subunit: (Microbial infection) The inactive form interacts with Toscana virus (TOS) NSS. {ECO:0000269|PubMed:23325696}.

Subunit: (Microbial infection) Interacts with herpes virus 8 protein v- IRF2; this interaction inhibits EIF2AK2 activation. {ECO:0000269|PubMed:11160738}.

Subunit: (Microbial infection) Interacts with vaccinia protein E3. {ECO:0000269|PubMed:25740987}.

Subunit: (Microbial infection) Interacts (via N-terminus) with Hepatitis C virus (HCV) mature core protein (via N-terminus); this interaction induces the autophosphorylation of EIF2AK2. {ECO:0000269|PubMed:17267064}.

Subunit: (Microbial infection) Interacts with Hepatitis C virus (HCV) non-structural protein 5A (NS5A); this interaction leads to disruption of EIF2AK2 dimerization by NS5A. {ECO:0000269|PubMed:16951545, ECO:0000269|PubMed:17451199, ECO:0000269|PubMed:9143277, ECO:0000269|PubMed:9710605}.

Subunit: (Microbial infection) Interacts with Hepatitis C virus (HCV) envelope glycoprotein E2; this interaction inhibits EIF2AK2 and blocks its inhibitory effect on protein synthesis and cell growth. {ECO:0000269|PubMed:9143277}.

Subunit: (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) nucleoprotein; this interaction inhibits EIF2AK2 phosphorylation of EIF2S1 and blocks EIF2AK2-mediated translation shutoff. {ECO:0000269|PubMed:20519500}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:22214662}. Nucleus {ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:21072047}. Cytoplasm, perinuclear region {ECO:0000269|PubMed:15121867}. Note=Nuclear localization is elevated in acute leukemia, myelodysplastic syndrome (MDS), melanoma, breast, colon, prostate and lung cancer patient samples or cell lines as well as neurocytes from advanced Creutzfeldt- Jakob disease patients. {ECO:0000269|PubMed:21072047}.

Tissue specificity: Highly expressed in thymus, spleen and bone marrow compared to non-hematopoietic tissues such as small intestine, liver, or kidney tissues. Colocalizes with GSK3B and TAU in the Alzheimer disease (AD) brain. Elevated levels seen in breast and colon carcinomas, and which correlates with tumor progression and invasiveness or risk of progression. {ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:23403623}.

Induction: By type I interferons. {ECO:0000269|PubMed:1695551}.

Ptm: Autophosphorylated on several Ser, Thr and Tyr residues. Autophosphorylation of Thr-451 is dependent on Thr-446 and is stimulated by dsRNA binding and dimerization. Autophosphorylation apparently leads to the activation of the kinase. Tyrosine autophosphorylation is essential for efficient dsRNA-binding, dimerization, and kinase activation. {ECO:0000269|PubMed:11152499, ECO:0000269|PubMed:11337501, ECO:0000269|PubMed:16179258, ECO:0000269|PubMed:16373505, ECO:0000269|PubMed:20685959, ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:21072047}.

Disease: Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN) [MIM:618877]: An autosomal dominant disorder characterized by global developmental delay apparent in early childhood, cognitive impairment, ataxia, poor or absent speech with dysarthria, hypotonia, hypertonia, extrapyramidal signs, tremor, and abnormal involuntary movements. Affected individuals also exhibit neurological regression in the setting of febrile illness or infection. Many patients have seizures. Brain imaging shows diffuse white matter abnormalities with poor myelination. {ECO:0000269|PubMed:32197074}. Note=The disease may be caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		IFN-induced dsRNA-dependent serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the innate immune response to viral infection (PubMed:18835251, PubMed:19507191, PubMed:19189853, PubMed:21123651, PubMed:21072047, PubMed:22948139, PubMed:23229543, PubMed:22381929). Inhibits viral replication via the integrated stress response (ISR): EIF2S1/eIF-2- alpha phosphorylation in response to viral infection converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, resulting to a shutdown of cellular and viral protein synthesis, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4 (PubMed:19189853, PubMed:21123651, PubMed:22948139, PubMed:23229543). Exerts its antiviral activity on a wide range of DNA and RNA viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) and herpes simplex virus 1 (HHV-1) (PubMed:11836380, PubMed:19189853, PubMed:20171114, PubMed:19840259, PubMed:21710204, PubMed:23115276, PubMed:23399035). Also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation: phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11 (PubMed:11836380, PubMed:22214662, PubMed:19229320). In addition to serine/threonine- protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteosomal degradation (PubMed:20395957). Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding proinflammatory cytokines and IFNs (PubMed:22948139, PubMed:23084476, PubMed:23372823). Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6 (PubMed:10848580, PubMed:15121867, PubMed:15229216). Can act as both a positive and negative regulator of the insulin signaling pathway (ISP) (PubMed:20685959). Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2) (PubMed:20685959). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes (PubMed:22801494). Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin (By similarity). {ECO:0000250\|UniProtKB:Q03963, ECO:0000269\|PubMed:10848580, ECO:0000269\|PubMed:11836380, ECO:0000269\|PubMed:15121867, ECO:0000269\|PubMed:15229216, ECO:0000269\|PubMed:18835251, ECO:0000269\|PubMed:19189853, ECO:0000269\|PubMed:19229320, ECO:0000269\|PubMed:19507191, ECO:0000269\|PubMed:19840259, ECO:0000269\|PubMed:20171114, ECO:0000269\|PubMed:20395957, ECO:0000269\|PubMed:20685959, ECO:0000269\|PubMed:21072047, ECO:0000269\|PubMed:21123651, ECO:0000269\|PubMed:21710204, ECO:0000269\|PubMed:22214662, ECO:0000269\|PubMed:22381929, ECO:0000269\|PubMed:22801494, ECO:0000269\|PubMed:22948139, ECO:0000269\|PubMed:23084476, ECO:0000269\|PubMed:23115276, ECO:0000269\|PubMed:23229543, ECO:0000269\|PubMed:23372823, ECO:0000269\|PubMed:23399035, ECO:0000269\|PubMed:32197074}.


Catalytic activity:		Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
Catalytic activity:		Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;
Catalytic activity:		Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2; Evidence={ECO:0000255\|PROSITE-ProRule:PRU10027};
Activity regulation:		Initially produced in an inactive form and is activated by binding to viral dsRNA, which causes dimerization and autophosphorylation in the activation loop and stimulation of function. ISGylation can activate it in the absence of viral infection. Can also be activated by heparin, proinflammatory stimuli, growth factors, cytokines, oxidative stress and the cellular protein PRKRA. Activity is markedly stimulated by manganese ions. Activation is blocked by the viral components HIV-1 Tat protein and large amounts of HIV-1 trans- activation response (TAR) RNA element as well as by the cellular proteins TARBP2, DUS2L, NPM1, NCK1 and ADAR. Down-regulated by Toscana virus (TOS) and Rift valley fever virus (RVFV) NSS which promote its proteasomal degradation. Inhibited by vaccinia virus protein E3, probably via dsRNA sequestering. {ECO:0000269\|PubMed:12882984, ECO:0000269\|PubMed:18096616, ECO:0000269\|PubMed:18835251, ECO:0000269\|PubMed:23229543, ECO:0000269\|PubMed:23325696}.
Subunit:		Homodimer. Interacts with STRBP (By similarity). Interacts with DNAJC3. Forms a complex with FANCA, FANCC, FANCG and HSP70. Interacts with ADAR/ADAR1. Interacts with IRS1 (By similarity). The inactive form interacts with NCK1 and GSN. Interacts (via the kinase catalytic domain) with STAT3 (via SH2 domain), TRAF2 (C-terminus), TRAF5 (C-terminus) and TRAF6 (C-terminus). Interacts with MAP2K6, IKBKB/IKKB, NPM1, TARBP2, NLRP1, NLRP3, NLRC4 and AIM2. Interacts (via DRBM 1 domain) with DUS2L (via DRBM domain). Interacts with DHX9 (via N-terminus) and this interaction is dependent upon activation of the kinase. {ECO:0000250\|UniProtKB:Q03963, ECO:0000269\|PubMed:10390359, ECO:0000269\|PubMed:10848580, ECO:0000269\|PubMed:11438532, ECO:0000269\|PubMed:12882984, ECO:0000269\|PubMed:15121867, ECO:0000269\|PubMed:15229216, ECO:0000269\|PubMed:15299030, ECO:0000269\|PubMed:16179258, ECO:0000269\|PubMed:17079286, ECO:0000269\|PubMed:18096616, ECO:0000269\|PubMed:18835251, ECO:0000269\|PubMed:19229320, ECO:0000269\|PubMed:22801494, ECO:0000269\|PubMed:23084476, ECO:0000269\|PubMed:25740987, ECO:0000269\|PubMed:8576172, ECO:0000269\|PubMed:9079663, ECO:0000269\|PubMed:9143277, ECO:0000269\|PubMed:9781815}.
Subunit:		(Microbial infection) Interacts with human herpes simplex virus 1 (HHV-1) protein US11 in an RNA-dependent manner. {ECO:0000269\|PubMed:11836380}.
Subunit:		(Microbial infection) The inactive form interacts with Toscana virus (TOS) NSS. {ECO:0000269\|PubMed:23325696}.
Subunit:		(Microbial infection) Interacts with herpes virus 8 protein v- IRF2; this interaction inhibits EIF2AK2 activation. {ECO:0000269\|PubMed:11160738}.
Subunit:		(Microbial infection) Interacts with vaccinia protein E3. {ECO:0000269\|PubMed:25740987}.
Subunit:		(Microbial infection) Interacts (via N-terminus) with Hepatitis C virus (HCV) mature core protein (via N-terminus); this interaction induces the autophosphorylation of EIF2AK2. {ECO:0000269\|PubMed:17267064}.
Subunit:		(Microbial infection) Interacts with Hepatitis C virus (HCV) non-structural protein 5A (NS5A); this interaction leads to disruption of EIF2AK2 dimerization by NS5A. {ECO:0000269\|PubMed:16951545, ECO:0000269\|PubMed:17451199, ECO:0000269\|PubMed:9143277, ECO:0000269\|PubMed:9710605}.
Subunit:		(Microbial infection) Interacts with Hepatitis C virus (HCV) envelope glycoprotein E2; this interaction inhibits EIF2AK2 and blocks its inhibitory effect on protein synthesis and cell growth. {ECO:0000269\|PubMed:9143277}.
Subunit:		(Microbial infection) Interacts with human respiratory syncytial virus (HRSV) nucleoprotein; this interaction inhibits EIF2AK2 phosphorylation of EIF2S1 and blocks EIF2AK2-mediated translation shutoff. {ECO:0000269\|PubMed:20519500}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:15121867, ECO:0000269\|PubMed:21029237, ECO:0000269\|PubMed:22214662}. Nucleus {ECO:0000269\|PubMed:21029237, ECO:0000269\|PubMed:21072047}. Cytoplasm, perinuclear region {ECO:0000269\|PubMed:15121867}. Note=Nuclear localization is elevated in acute leukemia, myelodysplastic syndrome (MDS), melanoma, breast, colon, prostate and lung cancer patient samples or cell lines as well as neurocytes from advanced Creutzfeldt- Jakob disease patients. {ECO:0000269\|PubMed:21072047}.
Tissue specificity:		Highly expressed in thymus, spleen and bone marrow compared to non-hematopoietic tissues such as small intestine, liver, or kidney tissues. Colocalizes with GSK3B and TAU in the Alzheimer disease (AD) brain. Elevated levels seen in breast and colon carcinomas, and which correlates with tumor progression and invasiveness or risk of progression. {ECO:0000269\|PubMed:21029237, ECO:0000269\|PubMed:23403623}.
Induction:		By type I interferons. {ECO:0000269\|PubMed:1695551}.
Ptm:		Autophosphorylated on several Ser, Thr and Tyr residues. Autophosphorylation of Thr-451 is dependent on Thr-446 and is stimulated by dsRNA binding and dimerization. Autophosphorylation apparently leads to the activation of the kinase. Tyrosine autophosphorylation is essential for efficient dsRNA-binding, dimerization, and kinase activation. {ECO:0000269\|PubMed:11152499, ECO:0000269\|PubMed:11337501, ECO:0000269\|PubMed:16179258, ECO:0000269\|PubMed:16373505, ECO:0000269\|PubMed:20685959, ECO:0000269\|PubMed:21029237, ECO:0000269\|PubMed:21072047}.
Disease:		Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN) [MIM:618877]: An autosomal dominant disorder characterized by global developmental delay apparent in early childhood, cognitive impairment, ataxia, poor or absent speech with dysarthria, hypotonia, hypertonia, extrapyramidal signs, tremor, and abnormal involuntary movements. Affected individuals also exhibit neurological regression in the setting of febrile illness or infection. Many patients have seizures. Brain imaging shows diffuse white matter abnormalities with poor myelination. {ECO:0000269\|PubMed:32197074}. Note=The disease may be caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily. {ECO:0000255\|PROSITE-ProRule:PRU00159}.