peripheral plasma membrane protein CASK; hCASK; Ca+2/calmodulin-dependent serine protein kinase; protein lin-2 homolog (CASK, LIN2)

Function

• multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring & ion channel trafficking
• contributes to neural development & regulation of gene expression via interaction with the transcription factor TRB1
• binds to cell-surface proteins, including
  • amyloid precursor protein (APP)
  • neurexins
  • syndecans
  • actin-binding band 4.1 protein
• may mediate a link between the extracellular matrix & the actin cytoskeleton via its interaction with syndecan & with the actin/spectrin-binding protein 4.1
• differs from archetypal CaMK members in that the kinase domain exhibits a constitutively active conformation & the autoinhibitory region does not engage in direct contact with the ATP-binding cleft, although it still binds Ca+2/CAM
• binds WHRN & NRXN1 cytosolic tail
• interacts with CASKIN1, APBA1, LIN7(A/B/C) & L27 domain of DLG1 & isoform 2 of DLG4 (putative)
• CASK & LIN7 form two mutually exclusive tripartite complexes with APBA1 or CASKIN1 (putative)
• interacts with FCHSD2
• interacts with TSPYL2
• part of a complex containing CASK, TRB1 & TSPYL2 (putative)
• interacts with KIRREL3

Kinetic parameters:

• KM=563 uM for ATP

Cofactor:

• unlike other protein kinases, does not require a divalent cation such as Mg+2 for catalytic activity

Structure

• the first L27 domain binds DLG1 & the second L27 domain probably binds LIN7 (putative)
• the protein kinase domain mediates the interaction with FCHSD2
• in the N-terminal section; belongs to the protein kinase superfamily, CAMK Ser/Thr protein kinase family, CaMK subfamily
• belongs to the MAGUK family
• contains 1 guanylate kinase-like domain
• contains 2 L27 domains
• contains 1 PDZ domain (DHR domain)
• contains 1 protein kinase domain
• contains 1 SH3 domain

Compartment

• nucleus (putative). cytoplasm
• cell membrane; peripheral membrane protein

Alternative splicing

named isoforms=6

Expression

• ubiquitous
• expression is significantly greater in brain relative to kidney, lung, & liver & in fetal brain & kidney relative to lung & liver

Pathology

• defects in CASK are the cause of
  • mental retardation X-linked CASK-related (MRXCASK)
  • FG syndrome type 4

More general terms

• guanylate kinase
• serine/threonine kinase

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=8573
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:8573
• OMIM: https://mirror.omim.org/entry/300172
• OMIM: https://mirror.omim.org/entry/300422
• OMIM: https://mirror.omim.org/entry/300749
• UniProt: http://www.uniprot.org/uniprot/O14936.html