High impact information on CAMK2N1

• Two isoforms of ICAP-1, a 200-amino acid protein (ICAP-1alpha) and a shorter 150-amino acid protein (ICAP-1beta), derived from alternatively spliced mRNA, are expressed in most cells [1].
• ICAP-1alpha is a phosphoprotein and the extent of its phosphorylation is regulated by the cell-matrix interaction [1].
• Indeed, talin and ICAP1-alpha bind to integrin beta tails by means of a PTB domain-NPXY ligand interaction [2].
• ICAP-1 alpha induced a rapid disruption of focal adhesions, which may result from the ability of ICAP-1 alpha to inhibit the association of beta(1A) integrin with talin, which is crucial for the assembly of these structures [3].
• Altogether, these results suggest that ICAP-1 alpha plays a key role in cell adhesion by acting as a negative regulator of beta(1) integrin avidity [3].

Biological context of CAMK2N1

• The point mutation T38D localized within the optimal CaMKII recognition motif of ICAP-1alpha results in a strong defect in cell spreading which cannot be overcome by the inhibition of the endogenous CaMKII [4].
• These findings indicate that Icap1 alpha is a PTB domain protein, which recognizes the NPXY motif of beta(1) integrin [5].
• Alanine scanning mutagenesis of this region revealed that Val(787), Val(790), and (792)NPKY(795) are critical for Icap1 alpha binding [5].
• The up-regulation of CaMKIINalpha expression was specific for the fear memory because the context alone and a shock control did not induce any variation of transcription level [6].
• Here we investigated whether or not CaMKIINalpha and CaMKIINbeta gene expressions are regulated in the mouse hippocampus and amygdala after background contextual fear conditioning [6].

Anatomical context of CAMK2N1

• Here, we demonstrate that, despite its ability to interact with beta(1A) integrin, ICAP-1 alpha is not recruited in focal adhesions, whereas it is colocalized with the integrin at the ruffling edges of the cells [3].
• This direct interaction was confirmed in vitro, using purified recombinant ICAP-1alpha and nm23-H2, and by co-immunoprecipitation from CHO cell lysates over-expressing ICAP-1alpha [7].
• The physiological relevance of this interaction is provided by confocal fluorescence microscopy, which shows that ICAP-1alpha and nm23-H2 are co-localized in lamellipodia during the early stages of cell spreading [7].
• Quantification of in situ hybridization signals showed that CaMKIINalpha expression increased in hippocampal area CA1, in the dentate gyrus (DG) and in the lateral amygdala (LA) 30 min after training [6].

Associations of CAMK2N1 with chemical compounds

• The regulation of ICAP-1alpha phosphorylation by the cell-matrix interaction suggests an important role of ICAP-1 during integrin-dependent cell adhesion [1].
• First, an enhancement of ICAP-1alpha phosphorylation is observed when cells were plated on fibronectin-coated but not on nonspecific poly-L-lysine-coated surface [1].

Physical interactions of CAMK2N1

• Integrin cytoplasmic domain-associated protein 1alpha (ICAP-1alpha ) interacts directly with the metastasis suppressor nm23-H2, and both proteins are targeted to newly formed cell adhesion sites upon integrin engagement [7].

Enzymatic interactions of CAMK2N1

• Conversely, the mutation T38A produces an analog of ICAP-1alpha that cannot be phosphorylated and that stimulates cell spreading on fibronectin to a similar extent when CaMKII is inhibited [4].

Other interactions of CAMK2N1

• Among those, the integrin cytoplasmic domain-associated protein 1alpha (ICAP-1alpha) has been shown to interact specifically with the beta(1) integrin cytoplasmic domain [7].
• This finding represents the first evidence that the tumor suppressor nm23-H2 could act on beta(1) integrin-mediated cell adhesion by interacting with one of the integrin partners, ICAP-1alpha [7].
• This paper provided evidence that the regulation of CHO cell adhesion on fibronectin by calcium/calmodulin-dependent protein kinase II (CaMKII) is mediated through the recently described integrin cytoplasmic domain associated protein-1alpha (ICAP-1alpha) [4].

Analytical, diagnostic and therapeutic context of CAMK2N1

• Site-directed mutagenesis showed that Leu(135), Ile(138), and Ile(139) of Icap1 alpha, residues predicted by the model to be in close proximity to (792)NPKY(795), and Leu(82) and Tyr(144), residues expected to form a hydrophobic pocket near Val(787), are required for the Icap1 alpha-beta(1) integrin interaction [5].
• Quantitative real-time PCR revealed that the hippocampal expression of CaMKIINalpha mRNA was up-regulated 30 and 60 min after conditioning [6].

References