ID CSKP_HUMAN Reviewed; 926 AA. AC O14936; A6NES1; B7ZKY0; O43215; Q17RI4; Q59HA0; Q5VT16; Q5VT17; AC Q5VT18; Q5VT19; Q66T42; Q9BYH6; Q9NYB2; Q9NYB3; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 17-APR-2007, sequence version 3. DT 31-JUL-2019, entry version 215. DE RecName: Full=Peripheral plasma membrane protein CASK; DE Short=hCASK; DE EC=2.7.11.1; DE AltName: Full=Calcium/calmodulin-dependent serine protein kinase; DE AltName: Full=Protein lin-2 homolog; GN Name=CASK; Synonyms=LIN2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND INTERACTION WITH SDC2 AND RP EPB41. RC TISSUE=Brain, Liver, and Lung; RX PubMed=9660868; DOI=10.1083/jcb.142.1.129; RA Cohen A.R., Woods D.F., Marfatia S.M., Walther Z., Chishti A.H., RA Anderson J.M.; RT "Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to RT the basolateral membrane of epithelial cells."; RL J. Cell Biol. 142:129-138(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3). RA Zha D., Hu G.; RT "The human homolog of the rat CASK, Drosophila Camguk and C.elegans RT Lin-2 genes."; RL Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5). RC TISSUE=Kidney; RA Ding L., Saijo K., Kawai K., Akaza H., Ugai H., Yokoyama K.K., RA Ohno T.; RT "Putative alternative splicing form of human CASK mRNA (partial RT codes)."; RL Submitted (FEB-2000) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RC TISSUE=Colon carcinoma; RA Yan Y., Merlin D.; RT "Caco2-BBE calcium/calmodulin-dependent serine protein kinase."; RL Submitted (AUG-2004) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15772651; DOI=10.1038/nature03440; RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S., RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., RA Williams G., Williams L., Williamson A., Williamson H., Wilming L., RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence of the human X chromosome."; RL Nature 434:325-337(2005). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 5-926 (ISOFORM 2). RC TISSUE=Brain; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 173-926 (ISOFORM 1), NUCLEOTIDE SEQUENCE RP [MRNA] OF 27-926 (ISOFORM 3), AND TISSUE SPECIFICITY. RC TISSUE=Fetus; RX PubMed=11003712; DOI=10.1007/s003350010170; RA Stevenson D., Laverty H.G., Wenwieser S., Douglas M., Wilson J.B.; RT "Mapping and expression analysis of the human CASK gene."; RL Mamm. Genome 11:934-937(2000). RN [9] RP INTERACTION WITH KIRREL3. RX PubMed=19012874; DOI=10.1016/j.ajhg.2008.10.020; RA Bhalla K., Luo Y., Buchan T., Beachem M.A., Guzauskas G.F., Ladd S., RA Bratcher S.J., Schroer R.J., Balsamo J., DuPont B.R., Lilien J., RA Srivastava A.K.; RT "Alterations in CDH15 and KIRREL3 in patients with mild to severe RT intellectual disability."; RL Am. J. Hum. Genet. 83:703-713(2008). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-51, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-313, PHOSPHORYLATION RP [LARGE SCALE ANALYSIS] AT SER-571 (ISOFORM 3), PHOSPHORYLATION [LARGE RP SCALE ANALYSIS] AT SER-577 (ISOFORM 4), PHOSPHORYLATION [LARGE SCALE RP ANALYSIS] AT SER-192 (ISOFORM 5), AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., RA Wang L., Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human RT liver phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [12] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 489-572. RX PubMed=9546224; DOI=10.1038/nsb0498-317; RA Daniels D.L., Cohen A.R., Anderson J.M., Bruenger A.T.; RT "Crystal structure of the hCASK PDZ domain reveals the structural RT basis of class II PDZ domain target recognition."; RL Nat. Struct. Biol. 5:317-325(1998). RN [13] RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 1-337 IN COMPLEX WITH AMP, RP COFACTOR, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, RP PHOSPHORYLATION OF NRXN1, AND PHOSPHORYLATION AT SER-151 AND SER-155. RX PubMed=18423203; DOI=10.1016/j.cell.2008.02.036; RA Mukherjee K., Sharma M., Urlaub H., Bourenkov G.P., Jahn R., RA Suedhof T.C., Wahl M.C.; RT "CASK functions as a Mg2+-independent neurexin kinase."; RL Cell 133:328-339(2008). RN [14] RP VARIANT [LARGE SCALE ANALYSIS] VAL-96. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E., RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [15] RP INVOLVEMENT IN MICPCH SYNDROME. RX PubMed=19165920; DOI=10.1038/ng.194; RA Najm J., Horn D., Wimplinger I., Golden J.A., Chizhikov V.V., Sudi J., RA Christian S.L., Ullmann R., Kuechler A., Haas C.A., Flubacher A., RA Charnas L.R., Uyanik G., Frank U., Klopocki E., Dobyns W.B., RA Kutsche K.; RT "Mutations of CASK cause an X-linked brain malformation phenotype with RT microcephaly and hypoplasia of the brainstem and cerebellum."; RL Nat. Genet. 40:1065-1067(2008). RN [16] RP ERRATUM. RA Najm J., Horn D., Wimplinger I., Golden J.A., Chizhikov V.V., Sudi J., RA Christian S.L., Ullmann R., Kuechler A., Haas C.A., Flubacher A., RA Charnas L.R., Uyanik G., Frank U., Klopocki E., Dobyns W.B., RA Kutsche K.; RL Nat. Genet. 40:1384-1384(2008). RN [17] RP VARIANT FGS4 LEU-28, AND CHARACTERIZATION OF VARIANT FGS4 LEU-28. RX PubMed=19200522; DOI=10.1016/j.ajhg.2008.12.018; RA Piluso G., D'Amico F., Saccone V., Bismuto E., Rotundo I.L., RA Di Domenico M., Aurino S., Schwartz C.E., Neri G., Nigro V.; RT "A missense mutation in CASK causes FG syndrome in an Italian RT family."; RL Am. J. Hum. Genet. 84:162-177(2009). RN [18] RP VARIANTS [LARGE SCALE ANALYSIS] MICPCH HIS-268; SER-396 AND GLY-710. RX PubMed=19377476; DOI=10.1038/ng.367; RA Tarpey P.S., Smith R., Pleasance E., Whibley A., Edkins S., Hardy C., RA O'Meara S., Latimer C., Dicks E., Menzies A., Stephens P., Blow M., RA Greenman C., Xue Y., Tyler-Smith C., Thompson D., Gray K., Andrews J., RA Barthorpe S., Buck G., Cole J., Dunmore R., Jones D., Maddison M., RA Mironenko T., Turner R., Turrell K., Varian J., West S., Widaa S., RA Wray P., Teague J., Butler A., Jenkinson A., Jia M., Richardson D., RA Shepherd R., Wooster R., Tejada M.I., Martinez F., Carvill G., RA Goliath R., de Brouwer A.P., van Bokhoven H., Van Esch H., Chelly J., RA Raynaud M., Ropers H.H., Abidi F.E., Srivastava A.K., Cox J., Luo Y., RA Mallya U., Moon J., Parnau J., Mohammed S., Tolmie J.L., RA Shoubridge C., Corbett M., Gardner A., Haan E., Rujirabanjerd S., RA Shaw M., Vandeleur L., Fullston T., Easton D.F., Boyle J., RA Partington M., Hackett A., Field M., Skinner C., Stevenson R.E., RA Bobrow M., Turner G., Schwartz C.E., Gecz J., Raymond F.L., RA Futreal P.A., Stratton M.R.; RT "A systematic, large-scale resequencing screen of X-chromosome coding RT exons in mental retardation."; RL Nat. Genet. 41:535-543(2009). RN [19] RP VARIANT 19-GLY--TYR-926 DEL. RX PubMed=23662938; DOI=10.1111/epi.12203; RA Kodera H., Kato M., Nord A.S., Walsh T., Lee M., Yamanaka G., RA Tohyama J., Nakamura K., Nakagawa E., Ikeda T., Ben-Zeev B., Lev D., RA Lerman-Sagie T., Straussberg R., Tanabe S., Ueda K., Amamoto M., RA Ohta S., Nonoda Y., Nishiyama K., Tsurusaki Y., Nakashima M., RA Miyake N., Hayasaka K., King M.C., Matsumoto N., Saitsu H.; RT "Targeted capture and sequencing for detection of mutations causing RT early onset epileptic encephalopathy."; RL Epilepsia 54:1262-1269(2013). CC -!- FUNCTION: Multidomain scaffolding protein with a role in synaptic CC transmembrane protein anchoring and ion channel trafficking. CC Contributes to neural development and regulation of gene CC expression via interaction with the transcription factor TBR1. CC Binds to cell-surface proteins, including amyloid precursor CC protein, neurexins and syndecans. May mediate a link between the CC extracellular matrix and the actin cytoskeleton via its CC interaction with syndecan and with the actin/spectrin-binding CC protein 4.1. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; CC EC=2.7.11.1; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.1; CC -!- COFACTOR: CC Note=Unlike other protein kinases, does not require a divalent CC cation such as magnesium for catalytic activity. CC {ECO:0000269|PubMed:18423203}; CC -!- ACTIVITY REGULATION: Differs from archetypal CaMK members in that CC the kinase domain exhibits a constitutively active conformation CC and the autoinhibitory region does not engage in direct contact CC with the ATP-binding cleft, although it still binds Ca(2+)/CAM. CC {ECO:0000269|PubMed:18423203}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=563 uM for ATP {ECO:0000269|PubMed:18423203}; CC Note=Kinetics of autophosphorylation assay were measured, rather CC than phosphorylation of an exogenous substrate.; CC -!- SUBUNIT: CASK and LIN7 form two mutually exclusive tripartite CC complexes with APBA1 or CASKIN1 (By similarity). Forms a CC heterotrimeric complex with DLG1 and LIN7B via their L27 domains CC (By similarity). Identified in a complex with ACTN4, IQGAP1, CC MAGI2, NPHS1, SPTAN1 and SPTBN1 (By similarity). Part of a complex CC containing CASK, TBR1 and TSPYL2 (By similarity). Interacts with CC WHRN (By similarity). Interacts (via the PDZ, SH3 and guanylate CC kinase-like domains) with NRXN1 (via C-terminus) (By similarity). CC Interacts with CASKIN1, APBA1, LIN7(A/B/C) and L27 domain of DLG1 CC and isoform 2 of DLG4 (By similarity). Interacts with FCHSD2 (By CC similarity). Interacts with KIRREL3 (PubMed:19012874). Interacts CC with TBR1 (By similarity). Interacts with TSPYL2 (By similarity). CC {ECO:0000250, ECO:0000250|UniProtKB:O70589, CC ECO:0000250|UniProtKB:Q62915, ECO:0000269|PubMed:18423203, CC ECO:0000269|PubMed:19012874, ECO:0000269|PubMed:9660868}. CC -!- INTERACTION: CC Q8WXD9:CASKIN1; NbExp=4; IntAct=EBI-1215506, EBI-970261; CC Q12929:EPS8; NbExp=3; IntAct=EBI-1215506, EBI-375576; CC P41134:ID1; NbExp=3; IntAct=EBI-1215506, EBI-1215527; CC O14910:LIN7A; NbExp=6; IntAct=EBI-1215506, EBI-2513988; CC Q63373:Nrxn1 (xeno); NbExp=3; IntAct=EBI-1215506, EBI-1780696; CC Q9Y2J0:RPH3A; NbExp=3; IntAct=EBI-1215506, EBI-1216802; CC P34741:SDC2; NbExp=2; IntAct=EBI-1215506, EBI-1172957; CC Q9H788:SH2D4A; NbExp=3; IntAct=EBI-1215506, EBI-747035; CC Q13425:SNTB2; NbExp=2; IntAct=EBI-1215506, EBI-80411; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q62915}. CC Cytoplasm {ECO:0000250|UniProtKB:Q62915}. Cell membrane CC {ECO:0000250|UniProtKB:Q62915}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:Q62915}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=1; CC IsoId=O14936-1; Sequence=Displayed; CC Name=2; CC IsoId=O14936-2; Sequence=VSP_024426; CC Name=3; CC IsoId=O14936-3; Sequence=VSP_024422, VSP_024424; CC Note=Contains a phosphoserine at position 571. CC {ECO:0000244|PubMed:24275569}; CC Name=4; CC IsoId=O14936-4; Sequence=VSP_024424, VSP_024426; CC Note=Contains a phosphoserine at position 577. CC {ECO:0000244|PubMed:24275569}; CC Name=5; CC IsoId=O14936-5; Sequence=VSP_024421, VSP_024423, VSP_024424; CC Note=Contains a phosphoserine at position 192. CC {ECO:0000244|PubMed:24275569}; CC Name=6; CC IsoId=O14936-6; Sequence=VSP_024425, VSP_024426; CC Note=Gene prediction confirmed by EST data.; CC -!- TISSUE SPECIFICITY: Ubiquitous. Expression is significantly CC greater in brain relative to kidney, lung, and liver and in fetal CC brain and kidney relative to lung and liver. CC {ECO:0000269|PubMed:11003712}. CC -!- DOMAIN: The first L27 domain binds DLG1 and the second L27 domain CC probably binds LIN7. {ECO:0000250}. CC -!- DOMAIN: The protein kinase domain mediates the interaction with CC FCHSD2. CC -!- DISEASE: Mental retardation and microcephaly with pontine and CC cerebellar hypoplasia (MICPCH) [MIM:300749]: A disorder CC characterized by significantly below average general intellectual CC functioning associated with impairments in adaptive behavior and CC manifested during the developmental period. Affected individuals CC can manifest a severe phenotype consisting of severe intellectual CC deficit, congenital or postnatal microcephaly, disproportionate CC brainstem and cerebellar hypoplasia. A milder phenotype consists CC of mental retardation alone or associated with nystagmus. CC {ECO:0000269|PubMed:19165920, ECO:0000269|PubMed:19377476}. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. CC -!- DISEASE: FG syndrome 4 (FGS4) [MIM:300422]: FG syndrome (FGS) is CC an X-linked disorder characterized by mental retardation, relative CC macrocephaly, hypotonia and constipation. CC {ECO:0000269|PubMed:19200522}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- SIMILARITY: In the N-terminal section; belongs to the protein CC kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK CC subfamily. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the MAGUK family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF032119; AAB88125.1; -; mRNA. DR EMBL; AF035582; AAB88198.1; -; mRNA. DR EMBL; AB039327; BAB12252.2; -; mRNA. DR EMBL; AY705392; AAU10527.1; -; mRNA. DR EMBL; AL158144; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL353691; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL445239; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL603754; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL627402; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC117311; AAI17312.1; -; mRNA. DR EMBL; BC143454; AAI43455.1; -; mRNA. DR EMBL; AB208859; BAD92096.1; -; mRNA. DR EMBL; AF262404; AAF72666.1; -; mRNA. DR EMBL; AF262405; AAF72667.1; -; mRNA. DR CCDS; CCDS14257.1; -. [O14936-2] DR CCDS; CCDS48094.1; -. [O14936-3] DR CCDS; CCDS48095.1; -. [O14936-4] DR RefSeq; NP_001119526.1; NM_001126054.2. [O14936-4] DR RefSeq; NP_001119527.1; NM_001126055.2. [O14936-3] DR RefSeq; NP_003679.2; NM_003688.3. [O14936-2] DR PDB; 1KGD; X-ray; 1.31 A; A=739-914. DR PDB; 1KWA; X-ray; 1.93 A; A/B=487-572. DR PDB; 1ZL8; NMR; -; B=403-456. DR PDB; 3C0G; X-ray; 2.19 A; A/B=1-337. DR PDB; 3C0H; X-ray; 2.30 A; A/B=1-337. DR PDB; 3C0I; X-ray; 1.85 A; A=1-337. DR PDB; 3MFR; X-ray; 2.00 A; A=1-337. DR PDB; 3MFS; X-ray; 2.10 A; A=1-337. DR PDB; 3MFT; X-ray; 2.20 A; A=1-337. DR PDB; 3MFU; X-ray; 2.30 A; A=1-337. DR PDB; 3TAC; X-ray; 2.20 A; A=1-345. DR PDBsum; 1KGD; -. DR PDBsum; 1KWA; -. DR PDBsum; 1ZL8; -. DR PDBsum; 3C0G; -. DR PDBsum; 3C0H; -. DR PDBsum; 3C0I; -. DR PDBsum; 3MFR; -. DR PDBsum; 3MFS; -. DR PDBsum; 3MFT; -. DR PDBsum; 3MFU; -. DR PDBsum; 3TAC; -. DR SMR; O14936; -. DR BioGrid; 114141; 106. DR CORUM; O14936; -. DR DIP; DIP-38727N; -. DR ELM; O14936; -. DR IntAct; O14936; 56. DR MINT; O14936; -. DR STRING; 9606.ENSP00000367408; -. DR BindingDB; O14936; -. DR ChEMBL; CHEMBL1908381; -. DR DrugBank; DB01942; Formic Acid. DR iPTMnet; O14936; -. DR PhosphoSitePlus; O14936; -. DR SwissPalm; O14936; -. DR BioMuta; CASK; -. DR EPD; O14936; -. DR jPOST; O14936; -. DR MaxQB; O14936; -. DR PaxDb; O14936; -. DR PeptideAtlas; O14936; -. DR PRIDE; O14936; -. DR ProteomicsDB; 48318; -. [O14936-1] DR ProteomicsDB; 48319; -. [O14936-2] DR ProteomicsDB; 48320; -. [O14936-3] DR ProteomicsDB; 48321; -. [O14936-4] DR ProteomicsDB; 48322; -. [O14936-5] DR ProteomicsDB; 48323; -. [O14936-6] DR TopDownProteomics; O14936-5; -. [O14936-5] DR DNASU; 8573; -. DR Ensembl; ENST00000378154; ENSP00000367396; ENSG00000147044. [O14936-6] DR Ensembl; ENST00000378163; ENSP00000367405; ENSG00000147044. [O14936-1] DR Ensembl; ENST00000421587; ENSP00000400526; ENSG00000147044. [O14936-4] DR Ensembl; ENST00000644347; ENSP00000494183; ENSG00000147044. [O14936-3] DR Ensembl; ENST00000645566; ENSP00000494788; ENSG00000147044. [O14936-2] DR GeneID; 8573; -. DR KEGG; hsa:8573; -. DR UCSC; uc004dfl.5; human. [O14936-1] DR CTD; 8573; -. DR DisGeNET; 8573; -. DR GeneCards; CASK; -. DR GeneReviews; CASK; -. DR HGNC; HGNC:1497; CASK. DR HPA; CAB001949; -. DR HPA; HPA023857; -. DR MalaCards; CASK; -. DR MIM; 300172; gene. DR MIM; 300422; phenotype. DR MIM; 300749; phenotype. DR neXtProt; NX_O14936; -. DR OpenTargets; ENSG00000147044; -. DR Orphanet; 1934; Early infantile epileptic encephalopathy. DR Orphanet; 323; NON RARE IN EUROPE: FG syndrome phenotypic spectrum. DR Orphanet; 163937; X-linked intellectual disability, Najm type. DR PharmGKB; PA26081; -. DR eggNOG; KOG0033; Eukaryota. DR eggNOG; KOG0609; Eukaryota. DR eggNOG; COG0194; LUCA. DR GeneTree; ENSGT00940000155600; -. DR InParanoid; O14936; -. DR KO; K06103; -. DR OMA; VCTASQW; -. DR OrthoDB; 1318335at2759; -. DR PhylomeDB; O14936; -. DR TreeFam; TF314263; -. DR BRENDA; 2.7.11.1; 2681. DR BRENDA; 2.7.4.8; 2681. DR Reactome; R-HSA-212676; Dopamine Neurotransmitter Release Cycle. DR Reactome; R-HSA-3000170; Syndecan interactions. DR Reactome; R-HSA-373753; Nephrin family interactions. DR Reactome; R-HSA-6794361; Neurexins and neuroligins. DR Reactome; R-HSA-9609736; Assembly and cell surface presentation of NMDA receptors. DR SABIO-RK; O14936; -. DR SignaLink; O14936; -. DR SIGNOR; O14936; -. DR ChiTaRS; CASK; human. DR EvolutionaryTrace; O14936; -. DR GeneWiki; CASK; -. DR GenomeRNAi; 8573; -. DR PRO; PR:O14936; -. DR Proteomes; UP000005640; Chromosome X. DR Bgee; ENSG00000147044; Expressed in 231 organ(s), highest expression level in epithelium of mammary gland. DR ExpressionAtlas; O14936; baseline and differential. DR Genevisible; O14936; HS. DR GO; GO:0015629; C:actin cytoskeleton; TAS:ProtInc. DR GO; GO:0005604; C:basement membrane; IDA:CACAO. DR GO; GO:0016323; C:basolateral plasma membrane; IEA:Ensembl. DR GO; GO:0005911; C:cell-cell junction; IDA:BHF-UCL. DR GO; GO:0060170; C:ciliary membrane; ISS:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005925; C:focal adhesion; HDA:UniProtKB. DR GO; GO:0005652; C:nuclear lamina; IDA:BHF-UCL. DR GO; GO:0016363; C:nuclear matrix; IDA:BHF-UCL. DR GO; GO:0005730; C:nucleolus; IDA:BHF-UCL. DR GO; GO:0005886; C:plasma membrane; TAS:ProtInc. DR GO; GO:0042734; C:presynaptic membrane; ISS:BHF-UCL. DR GO; GO:0098685; C:Schaffer collateral - CA1 synapse; IEA:Ensembl. DR GO; GO:0031982; C:vesicle; IEA:Ensembl. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0005516; F:calmodulin binding; IEA:UniProtKB-KW. DR GO; GO:0004385; F:guanylate kinase activity; TAS:ProtInc. DR GO; GO:0042043; F:neurexin family protein binding; IEA:Ensembl. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW. DR GO; GO:0070509; P:calcium ion import; IEA:Ensembl. DR GO; GO:0007155; P:cell adhesion; TAS:ProtInc. DR GO; GO:0001953; P:negative regulation of cell-matrix adhesion; IMP:BHF-UCL. DR GO; GO:0090288; P:negative regulation of cellular response to growth factor stimulus; IMP:BHF-UCL. DR GO; GO:0010839; P:negative regulation of keratinocyte proliferation; IDA:CACAO. DR GO; GO:0061045; P:negative regulation of wound healing; IMP:BHF-UCL. DR GO; GO:0007269; P:neurotransmitter secretion; TAS:Reactome. DR GO; GO:0090280; P:positive regulation of calcium ion import; IEA:Ensembl. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:2000300; P:regulation of synaptic vesicle exocytosis; IEA:Ensembl. DR CDD; cd12081; SH3_CASK; 1. DR InterPro; IPR035473; CASK_SH3. DR InterPro; IPR008145; GK/Ca_channel_bsu. DR InterPro; IPR008144; Guanylate_kin-like_dom. DR InterPro; IPR020590; Guanylate_kinase_CS. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR014775; L27_C. DR InterPro; IPR004172; L27_dom. DR InterPro; IPR036892; L27_dom_sf. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR001478; PDZ. DR InterPro; IPR036034; PDZ_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR036028; SH3-like_dom_sf. DR InterPro; IPR001452; SH3_domain. DR Pfam; PF00625; Guanylate_kin; 1. DR Pfam; PF02828; L27; 2. DR Pfam; PF00595; PDZ; 1. DR Pfam; PF00069; Pkinase; 1. DR Pfam; PF07653; SH3_2; 1. DR SMART; SM00072; GuKc; 1. DR SMART; SM00569; L27; 2. DR SMART; SM00228; PDZ; 1. DR SMART; SM00326; SH3; 1. DR SUPFAM; SSF101288; SSF101288; 2. DR SUPFAM; SSF50044; SSF50044; 1. DR SUPFAM; SSF50156; SSF50156; 1. DR SUPFAM; SSF52540; SSF52540; 1. DR SUPFAM; SSF56112; SSF56112; 1. DR PROSITE; PS00856; GUANYLATE_KINASE_1; 1. DR PROSITE; PS50052; GUANYLATE_KINASE_2; 1. DR PROSITE; PS51022; L27; 2. DR PROSITE; PS50106; PDZ; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS50002; SH3; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Calmodulin-binding; KW Cell membrane; Complete proteome; Cytoplasm; Disease mutation; Kinase; KW Membrane; Mental retardation; Nucleotide-binding; Nucleus; KW Phosphoprotein; Polymorphism; Reference proteome; Repeat; KW Serine/threonine-protein kinase; SH3 domain; Transferase. FT CHAIN 1 926 Peripheral plasma membrane protein CASK. FT /FTId=PRO_0000094568. FT DOMAIN 12 276 Protein kinase. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT DOMAIN 343 398 L27 1. {ECO:0000255|PROSITE- FT ProRule:PRU00365}. FT DOMAIN 402 455 L27 2. {ECO:0000255|PROSITE- FT ProRule:PRU00365}. FT DOMAIN 489 564 PDZ. {ECO:0000255|PROSITE- FT ProRule:PRU00143}. FT DOMAIN 612 682 SH3. {ECO:0000255|PROSITE- FT ProRule:PRU00192}. FT DOMAIN 739 911 Guanylate kinase-like. FT {ECO:0000255|PROSITE-ProRule:PRU00100}. FT NP_BIND 18 26 ATP. {ECO:0000255|PROSITE- FT ProRule:PRU00100, ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT REGION 305 315 Calmodulin-binding. FT REGION 482 909 Required for interaction with NRXN1 (via FT C-terminal tail). FT {ECO:0000250|UniProtKB:Q62915}. FT ACT_SITE 141 141 {ECO:0000250}. FT BINDING 41 41 ATP. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT MOD_RES 51 51 Phosphoserine. FT {ECO:0000244|PubMed:23186163}. FT MOD_RES 151 151 Phosphoserine; by autocatalysis. FT {ECO:0000269|PubMed:18423203}. FT MOD_RES 155 155 Phosphoserine; by autocatalysis. FT {ECO:0000269|PubMed:18423203}. FT MOD_RES 182 182 Phosphothreonine. FT {ECO:0000250|UniProtKB:O70589}. FT MOD_RES 313 313 Phosphoserine. FT {ECO:0000244|PubMed:24275569}. FT VAR_SEQ 1 385 Missing (in isoform 5). FT {ECO:0000303|Ref.3}. FT /FTId=VSP_024421. FT VAR_SEQ 340 345 Missing (in isoform 3). FT {ECO:0000303|PubMed:11003712, FT ECO:0000303|Ref.2}. FT /FTId=VSP_024422. FT VAR_SEQ 386 386 L -> M (in isoform 5). FT {ECO:0000303|Ref.3}. FT /FTId=VSP_024423. FT VAR_SEQ 580 602 Missing (in isoform 3, isoform 4 and FT isoform 5). {ECO:0000303|PubMed:11003712, FT ECO:0000303|PubMed:15489334, FT ECO:0000303|Ref.2, ECO:0000303|Ref.3}. FT /FTId=VSP_024424. FT VAR_SEQ 603 614 Missing (in isoform 6). {ECO:0000305}. FT /FTId=VSP_024425. FT VAR_SEQ 719 723 Missing (in isoform 2, isoform 4 and FT isoform 6). {ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:9660868, FT ECO:0000303|Ref.4, ECO:0000303|Ref.7}. FT /FTId=VSP_024426. FT VARIANT 19 926 Missing (probable disease-associated FT mutation found in a patient with epilepsy FT and pontocerebellar hypoplasia). FT {ECO:0000269|PubMed:23662938}. FT /FTId=VAR_078710. FT VARIANT 28 28 R -> L (in FGS4; does not reveal FT significant alterations induced by the FT mutation substitution; causes a partial FT skipping of exon 2 of the protein; FT dbSNP:rs137852816). FT {ECO:0000269|PubMed:19200522}. FT /FTId=VAR_058719. FT VARIANT 96 96 G -> V (in a lung large cell carcinoma FT sample; somatic mutation). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041956. FT VARIANT 268 268 Y -> H (in MICPCH; dbSNP:rs137852817). FT {ECO:0000269|PubMed:19377476}. FT /FTId=VAR_062996. FT VARIANT 396 396 P -> S (in MICPCH; dbSNP:rs137852820). FT {ECO:0000269|PubMed:19377476}. FT /FTId=VAR_062997. FT VARIANT 710 710 D -> G (in MICPCH; dbSNP:rs137852818). FT {ECO:0000269|PubMed:19377476}. FT /FTId=VAR_062998. FT CONFLICT 401 401 P -> L (in Ref. 2; AAB88198). FT {ECO:0000305}. FT CONFLICT 479 479 D -> G (in Ref. 1; AAB88125, 3; BAB12252, FT 4; AAU10527 and 8; AAF72666/AAF72667). FT {ECO:0000305}. FT CONFLICT 675 675 P -> S (in Ref. 1; AAB88125 and 4; FT AAU10527). {ECO:0000305}. FT CONFLICT 780 780 K -> R (in Ref. 1; AAB88125 and 4; FT AAU10527). {ECO:0000305}. FT HELIX 8 11 {ECO:0000244|PDB:3C0I}. FT STRAND 12 20 {ECO:0000244|PDB:3C0I}. FT STRAND 22 31 {ECO:0000244|PDB:3C0I}. FT TURN 32 34 {ECO:0000244|PDB:3C0I}. FT STRAND 37 44 {ECO:0000244|PDB:3C0I}. FT HELIX 45 49 {ECO:0000244|PDB:3C0I}. FT STRAND 51 53 {ECO:0000244|PDB:3C0I}. FT HELIX 56 68 {ECO:0000244|PDB:3C0I}. FT STRAND 77 83 {ECO:0000244|PDB:3C0I}. FT STRAND 86 92 {ECO:0000244|PDB:3C0I}. FT HELIX 99 108 {ECO:0000244|PDB:3C0I}. FT HELIX 115 134 {ECO:0000244|PDB:3C0I}. FT HELIX 144 146 {ECO:0000244|PDB:3C0I}. FT STRAND 147 149 {ECO:0000244|PDB:3C0I}. FT STRAND 151 153 {ECO:0000244|PDB:3C0I}. FT STRAND 158 160 {ECO:0000244|PDB:3C0I}. FT HELIX 163 165 {ECO:0000244|PDB:3TAC}. FT STRAND 171 173 {ECO:0000244|PDB:3MFS}. FT HELIX 183 185 {ECO:0000244|PDB:3C0I}. FT HELIX 188 191 {ECO:0000244|PDB:3C0I}. FT HELIX 199 214 {ECO:0000244|PDB:3C0I}. FT HELIX 223 232 {ECO:0000244|PDB:3C0I}. FT HELIX 239 242 {ECO:0000244|PDB:3C0I}. FT HELIX 247 256 {ECO:0000244|PDB:3C0I}. FT TURN 261 263 {ECO:0000244|PDB:3C0I}. FT HELIX 267 271 {ECO:0000244|PDB:3C0I}. FT HELIX 274 277 {ECO:0000244|PDB:3C0I}. FT HELIX 279 282 {ECO:0000244|PDB:3C0I}. FT HELIX 289 302 {ECO:0000244|PDB:3C0I}. FT TURN 304 306 {ECO:0000244|PDB:3TAC}. FT HELIX 309 312 {ECO:0000244|PDB:3C0G}. FT STRAND 314 316 {ECO:0000244|PDB:3C0G}. FT HELIX 404 416 {ECO:0000244|PDB:1ZL8}. FT HELIX 423 431 {ECO:0000244|PDB:1ZL8}. FT HELIX 437 450 {ECO:0000244|PDB:1ZL8}. FT STRAND 489 495 {ECO:0000244|PDB:1KWA}. FT STRAND 497 499 {ECO:0000244|PDB:1KWA}. FT STRAND 503 506 {ECO:0000244|PDB:1KWA}. FT HELIX 510 512 {ECO:0000244|PDB:1KWA}. FT STRAND 513 518 {ECO:0000244|PDB:1KWA}. FT HELIX 523 527 {ECO:0000244|PDB:1KWA}. FT STRAND 535 539 {ECO:0000244|PDB:1KWA}. FT HELIX 544 546 {ECO:0000244|PDB:1KWA}. FT HELIX 549 558 {ECO:0000244|PDB:1KWA}. FT STRAND 561 568 {ECO:0000244|PDB:1KWA}. FT STRAND 741 745 {ECO:0000244|PDB:1KGD}. FT HELIX 752 762 {ECO:0000244|PDB:1KGD}. FT TURN 764 766 {ECO:0000244|PDB:1KGD}. FT TURN 784 786 {ECO:0000244|PDB:1KGD}. FT HELIX 793 801 {ECO:0000244|PDB:1KGD}. FT STRAND 805 811 {ECO:0000244|PDB:1KGD}. FT STRAND 814 819 {ECO:0000244|PDB:1KGD}. FT HELIX 820 828 {ECO:0000244|PDB:1KGD}. FT STRAND 832 836 {ECO:0000244|PDB:1KGD}. FT HELIX 839 841 {ECO:0000244|PDB:1KGD}. FT HELIX 842 845 {ECO:0000244|PDB:1KGD}. FT TURN 848 850 {ECO:0000244|PDB:1KGD}. FT STRAND 852 858 {ECO:0000244|PDB:1KGD}. FT HELIX 870 886 {ECO:0000244|PDB:1KGD}. FT HELIX 887 889 {ECO:0000244|PDB:1KGD}. FT STRAND 891 895 {ECO:0000244|PDB:1KGD}. FT HELIX 899 913 {ECO:0000244|PDB:1KGD}. SQ SEQUENCE 926 AA; 105123 MW; 6C02008CE52728BA CRC64; MADDDVLFED VYELCEVIGK GPFSVVRRCI NRETGQQFAV KIVDVAKFTS SPGLSTEDLK REASICHMLK HPHIVELLET YSSDGMLYMV FEFMDGADLC FEIVKRADAG FVYSEAVASH YMRQILEALR YCHDNNIIHR DVKPHCVLLA SKENSAPVKL GGFGVAIQLG ESGLVAGGRV GTPHFMAPEV VKREPYGKPV DVWGCGVILF ILLSGCLPFY GTKERLFEGI IKGKYKMNPR QWSHISESAK DLVRRMLMLD PAERITVYEA LNHPWLKERD RYAYKIHLPE TVEQLRKFNA RRKLKGAVLA AVSSHKFNSF YGDPPEELPD FSEDPTSSGL LAAERAVSQV LDSLEEIHAL TDCSEKDLDF LHSVFQDQHL HTLLDLYDKI NTKSSPQIRN PPSDAVQRAK EVLEEISCYP ENNDAKELKR ILTQPHFMAL LQTHDVVAHE VYSDEALRVT PPPTSPYLNG DSPESANGDM DMENVTRVRL VQFQKNTDEP MGITLKMNEL NHCIVARIMH GGMIHRQGTL HVGDEIREIN GISVANQTVE QLQKMLREMR GSITFKIVPS YRTQSSSCER DSPSTSRQSP ANGHSSTNNS VSDLPSTTQP KGRQIYVRAQ FEYDPAKDDL IPCKEAGIRF RVGDIIQIIS KDDHNWWQGK LENSKNGTAG LIPSPELQEW RVACIAMEKT KQEQQASCTW FGKKKKQYKD KYLAKHNAVF DQLDLVTYEE VVKLPAFKRK TLVLLGAHGV GRRHIKNTLI TKHPDRFAYP IPHTTRPPKK DEENGKNYYF VSHDQMMQDI SNNEYLEYGS HEDAMYGTKL ETIRKIHEQG LIAILDVEPQ ALKVLRTAEF APFVVFIAAP TITPGLNEDE SLQRLQKESD ILQRTYAHYF DLTIINNEID ETIRHLEEAV ELVCTAPQWV PVSWVY //