CNKSR2
Encyclopedia
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
.
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.
, and is implicated in ras signalling. It has been show 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.
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. 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. 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.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the CNKSR2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
CNKSR2 is a multidomain protein that functions as a scaffold protein to mediate the mitogen-activated protein kinase pathwaysMAPK/ERK pathway
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
downstream from Ras. This gene product is induced by vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
and inhibits apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
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.
Mechanism of action
It is the mammalian homolog of the Drosophilia gene Cnk, which is known to bind RafC-Raf
RAF proto-oncogene serine/threonine-protein kinase also known as proto-oncogene c-RAF or simply c-Raf is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein functions in the MAPK/ERK signal transduction pathway as part of a protein kinase cascade...
, and is implicated in ras signalling. It has been show 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.
It is known to have two isoforms, one of which binds PSD95
DLG4
PSD-95 also known as SAP-90 is a protein that in humans is encoded by the DLG4 gene....
and S-SCAM
MAGI2
Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 also known as membrane-associated guanylate kinase inverted 2 and atrophin-1-interacting protein 1 is an enzyme that in humans is encoded by the MAGI2 gene.- Function :The protein encoded by this gene interacts with...
(synaptic scaffolding molecule) through its PDZ domain
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals...
, 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
Pleckstrin homology domain
Pleckstrin homology domain is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton....
. It's synaptic localization is not known to be affected by NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
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
Synaptophysin
Synaptophysin also known as the major synaptic vesicle protein p38 is a protein that in humans is encoded by the SYP gene.-Genomics:...
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
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
, Pi3K
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
and insulin pathways. It was found to form a complex with MEK1
MAP2K1
Dual specificity mitogen-activated protein kinase kinase 1 is an enzyme that in humans is encoded by the MAP2K1 gene.- Function :The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein kinase kinase...
(Erk2, p38), MEK2
MAP2K2
Dual specificity mitogen-activated protein kinase kinase 2 is an enzyme that in humans is encoded by the MAP2K2 gene.- Function :The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is known to play a critical role in...
, cdk4
Cyclin-dependent kinase 4
Cyclin-dependent kinase 4 is part of the cyclin-dependent kinase family.It is regulated by Cyclin D.-Interactions:Cyclin-dependent kinase 4 has been shown to interact with SERTAD1, CDC37, CEBPA, PCNA, Cyclin D3, Cyclin D1, CDKN2C, MyoD, P16, CDKN2B, Drebrin-like and CDKN1B.-External links:...
, PI3k, the phosphatases PP2A
Protein Phosphatase 2
Protein phosphatase 2 , also known as PP2A, is an enzyme that in humans is encoded by the PPP2CA gene. The PP2A heterotrimeric protein phosphatase, is a ubiquitous and conserved Serine/Threonine phosphatase with broad substrate specificity and diverse cellular functions...
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
LRRC7
Leucine rich repeat containing 7 also known as LRRC7, Densin-180, or LAP1 is a protein which in humans is encoded by the LRRC7 gene.- Structure :...
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. This brings it into a complex with CamKII
Ca2+/calmodulin-dependent protein kinase
/calmodulin-dependent protein kinases II or CaM kinases II are serine/threonine-specific protein kinases that are regulated by the /calmodulin complex...
and β-catenin
Beta-catenin
Beta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
, and further to the binding partners of CNKSR2 suggest that CNKSR2 may have a role in dendritic branching.