CNKSR2

Connector enhancer of kinase suppressor of ras 2, also known as CNK homolog protein 2 (CNK2) or MAGUIN (membrane-associated guanylate kinase-interacting protein), is an enzyme that in humans is encoded by the CNKSR2 gene.^[5]

CNKSR2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2EAN, 3BS5
Identifiers
Aliases	CNKSR2, CNK2, KSR2, MAGUIN, connector enhancer of kinase suppressor of Ras 2, MRXSHG
External IDs	OMIM: 300724; MGI: 2661175; HomoloGene: 8956; GeneCards: CNKSR2; OMA:CNKSR2 - orthologs
Gene location (Human) Chr. X chromosome (human)[1] Band Xp22.12 Start 21,372,801 bp[1] End 21,654,695 bp[1]
Gene location (Mouse) Chr. X chromosome (mouse)[2] Band X|X F4 Start 156,604,432 bp[2] End 156,826,290 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Brodmann area 23 cerebellar cortex cerebellar hemisphere superior frontal gyrus primary visual cortex postcentral gyrus middle temporal gyrus right hemisphere of cerebellum buccal mucosa cell entorhinal cortex Top expressed in primary visual cortex superior frontal gyrus dentate gyrus of hippocampal formation granule cell nucleus accumbens prefrontal cortex genital tubercle hippocampus proper cerebellar cortex Region I of hippocampus proper dorsal striatum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function identical protein binding protein binding Cellular component cytoplasm neuron projection soma postsynaptic membrane extracellular exosome membrane postsynaptic density glutamatergic synapse extrinsic component of postsynaptic density membrane Biological process regulation of signal transduction postsynapse organization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 22866 245684 Ensembl ENSG00000149970 ENSMUSG00000025658 UniProt Q8WXI2 Q80YA9 RefSeq (mRNA) NM_001168647 NM_001168648 NM_001168649 NM_014927 NM_001330770 NM_001330771 NM_001330772 NM_001330773 NM_177751 NM_001310719 NM_001374835 RefSeq (protein) NP_001162118 NP_001162119 NP_001162120 NP_001317699 NP_001317700 NP_001317701 NP_001317702 NP_055742 NP_001297648 NP_808419 NP_001361764 Location (UCSC) Chr X: 21.37 – 21.65 Mb Chr X: 156.6 – 156.83 Mb PubMed search [3] [4]
Wikidata
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Function

CNKSR2 is a multidomain protein that functions as a scaffold protein to mediate the mitogen-activated protein kinase pathways downstream from Ras. This gene product is induced by vitamin D and inhibits apoptosis in certain cancer cells. It may also play a role in ternary complex assembly of synaptic proteins at the postsynaptic membrane and coupling of signal transduction to membrane/cytoskeletal remodeling.^[5]

Mechanism of action

It is the mammalian homolog of the Drosophila gene Cnk, which is known to bind Raf, and is implicated in ras signalling. It has been shown that CNKSR2 is also a Raf binding protein, and is assumed to function in bringing together the Ras signalling complex at the post synaptic density.^[6]

It is known to have two isoforms, one of which binds PSD95 and S-SCAM (synaptic scaffolding molecule) through its PDZ domain, and another which does not. Both of the isoforms are, however, known to be synaptically localized, and it is understood that this is mediated by the Pleckstrin homology domain. It's synaptic localization is not known to be affected by NMDA receptor activation. Overexpression of MAGUIN's C-terminal PDZ domain is known to repress synaptic localization of PSD95. In cultures, MAGUIN colocalizes with PSD95 and synaptophysin at puncta in neurites, and these puncta are first visible at 6DIV.

Proteomic work done on binding partners of Ksr2 suggests that the CNKSR2/KSR2 complex may play a role in mediating crosstalk between the MAPK, Pi3K and insulin pathways.^[7] It was found to form a complex with MEK1 (Erk2, p38), MEK2, cdk4, PI3k, the phosphatases PP2A and PP^, and also various translational, ribosomal, transport and structural proteins. It remains to be established how many of these are affected by CNKSR2, and whether this remains true for Ksr2 in the nervous system.

Densin-180 is another important synaptic protein found to interact with CNKSR2. It is known to bind at its C-terminal PDZ domain. In transfected cells, no association could be found between PSD95 and Densin-180 without the presence of CNKSR2.^[8] This brings it into a complex with CamKII and β-catenin, and further to the binding partners of CNKSR2 suggest that CNKSR2 may have a role in dendritic branching.

Mutation

Deletions of this gene on the X-chromosome of males leads to intellectual disability and epileptic seizures.^[9]