1. Gene Aliases

A-Kinase Interacting Protein 1, BCA3, A Kinase (PRKA) Interacting Protein 1, A-Kinase-Interacting Protein 1, Proline-Rich Protein BCA3, C11orf17, Breast Cancer-Associated Gene 3 Protein, Chromosome 11 Open Reading Frame 17, Breast Cancer Associated Gene 3, PKA-Interacting Protein, Koyt Binding Protein 1, Koyt Binding Protein 2, Koyt Binding Protein 3, C11ORF17 [https://www.genecards.org/cgi-bin/carddisp.pl?gene=AKIP1]

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

Interactions with text mining support

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

Regulation of NF-kappa B signaling: Nuclear factor kappa B (NF-kappa-B, NF-kappaB) is activated by a diverse range of stimuli including cytokines, ligands of pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs) in myeloid cells, antigen-activated TCR in T-cells and by DNA damage (reviewed in Yu H et al. 2020; Zhang T et al. 2021). NF-kappa-B regulates the transcription of genes that are involved in immune and inflammatory responses, cell cycle, cell proliferation and apoptosis (Bhatt D & Ghosh S 2014; Liu T et al. 2017; Yu H et al. 2020). In unstimulated cells, NF-kappaB is sequestered in the cytosol through interactions with a class of inhibitor proteins, called NF-kappaB inhibitors (IkBs, such as NFKBIA or NFKBIB) (Jacobs MD & Harrison SC 1998). IkBs mask the nuclear localization signal (NLS) of NF-kappaB preventing its nuclear translocation (Cervantes CF et al. 2011). A key event in NF-kappaB activation involves phosphorylation of IkBs by the IkB kinase (IKK) complex which consists of CHUK, IKBKB and IKBKG subunits (Israel A 2010). The activated NF-kappaB signaling is tightly controlled at multiple levels (Dorrington MG & Fraser IDC 2019; Prescott JA et al. 2021). Dysregulated NF-kappaB activity can cause tissue damage associated with inflammatory diseases and is also linked to tumorigenesis (Aggarwal BB & Sung B 2011; Liu T et al.2017; Barnabei L et al. 2021). The regulation of NF-kappaB is cell-type-, context- , and stimulus-dependent and is crucial for orchestrating specific cellular responses (Mussbacher M et al. 2019) [https://reactome.org/content/detail/R-HSA-9758274].

Signaling by WNT: WNT signaling pathways control a wide range of developmental and adult process in metozoans including cell proliferation, cell fate decisions, cell polarity and stem cell maintenance (reviewed in Saito-Diaz et al, 2013; MacDonald et al, 2009). The pathway is named for the WNT ligands, a large family of secreted cysteine-rich glycoproteins. At least 19 WNT members have been identified in humans and mice with distinct expression patterns during development (reviewed in Willert and Nusse, 2012). These ligands can activate at least three different downstream signaling cascades depending on which receptors they engage.

In the so-called 'canonical' WNT signaling pathway, WNT ligands bind one of the 10 human Frizzled (FZD) receptors in conjunction with the LRP5/6 co-receptors to activate a transcriptional cascade that controls processes such as cell fate, proliferation and self-renenwal of stem cells. Engagement of the FZD-LRP receptor by WNT ligand results in the stabilization and translocation of cytosolic beta-catenin to the nucleus where it is a co-activator for LEF (lymphoid enhancer-binding factor)- and TCF (T cell factor) -dependent transcription. In the absence of WNT ligand, cytosolic beta-catenin is phosphorylated by a degradation complex consisting of glycogen synthase kinase 3 (GSK3), casein kinase 1 (CK1), Axin and Adenomatous polyposis coli (APC), and subsequently ubiquitinated and degraded by the 26S proteasome (reviewed in Saito-Diaz et al, 2013; Kimmelman and Xu, 2006).

In addition to the beta-catenin-dependent transcriptional response, WNT signaling can also activate distinct non-transcriptional pathways that regulate cell migration and polarity. These beta-catenin-independent 'non-canonical' pathways signal through Frizzled receptors independently of LRP5/6, or occur through the tyrosine kinase receptors ROR and RYK (reviewed in Veeman et al, 2003; James et al, 2009). Non-canonical WNT pathways are best studied in Drosophila where the planar cell polarity (PCP) pathway controls the orientation of wing hairs and eye facets, but are also involved in processes such as convergent extension, neural tube closure, inner ear development and hair orientation in vertebrates and mammals(reviewed in Seifert and Mlodzik, 2007; Simons and Mlodzik, 2008). In the PCP pathway, binding of WNT ligand to the FZD receptor leads to activation of small Rho GTPases and JNK, which regulate the cytoskeleton and coordinate cell migration and polarity (reviewed in Lai et al, 2009; Schlessinger et al, 2009). In some cases, a FZD-WNT interaction increases intracellular calcium concentration and activates CaMK II and PKC; this WNT calcium pathway promotes cell migration and inhibits the canonical beta-catenin dependent transcriptional pathway (reviewed in Kuhl et al, 2000; Kohn and Moon, 2005; Rao et al 2010). Binding of WNT to ROR or RYK receptors also regulates cell migration, apparently through activation of JNK or SRC kinases, respectively, however the details of these pathways remain to be worked out (reviewed in Minami et al, 2010).

Although the WNT signaling pathways were originally viewed as discrete, linear pathways controlled by defined subsets of 'canonical' or 'non-canonical' ligands and receptors, the emerging evidence is challenging this notion. Instead, the specificity and the downstream response appear to depend on the particular cellular context and vary with species, tissue and stage of development (reviewed in van Amerongen and Nusse, 2009; Rao et al, 2010). [https://reactome.org/PathwayBrowser/#/R-HSA-195721&PATH=R-HSA-162582].

GO terms:

regulation of non-canonical NF-kappaB signal transduction [Any process that modulates the frequency, rate or extent of the non-canonical NF-kappaB signaling cascade. GO:1901222]

substrate adhesion-dependent cell spreading [The morphogenetic process that results in flattening of a cell as a consequence of its adhesion to a substrate. GO:0034446]

MSigDB Signatures:

DAVICIONI_MOLECULAR_ARMS_VS_ERMS_DN: Genes down-regulated in mARMS (molecular ARMS) compared to the mERMS (molecular ERMS) class of rhabdomyosarcoma tumors. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/DAVICIONI_MOLECULAR_ARMS_VS_ERMS_DN.htm]

7. Gene Descriptions

NCBI Gene Summary: This gene encodes a nuclear protein that interacts with protein kinase A catalytic subunit, and regulates the effect of the cAMP-dependent protein kinase signaling pathway on the NF-kappa-B activation cascade. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Oct 2011]

GeneCards Summary: AKIP1 (A-Kinase Interacting Protein 1) is a Protein Coding gene.

UniProtKB/Swiss-Prot Summary: Enhances NF-kappa-B transcriptional activity by regulating the nuclear localization of the NF-kappa-B subunit RELA and promoting the phosphorylation of RELA by PRKACA. Regulates the effect of the cAMP-dependent protein kinase signaling pathway on the NF-kappa-B activation cascade.

8. Cellular Location of Gene Product

Localized to the nucleoplasm. Predicted location: Intracellular [https://www.proteinatlas.org/ENSG00000166452/subcellular]

9. Mechanistic Information

Summary

The AKIP1 gene plays a crucial role in the heart's response to stress and injury, as evidenced by its upregulation in conditions like heart failure, hypertrophy, and cardiac stress [CS: 8]. AKIP1 facilitates activation of cellular survival mechanisms and tissue repair by increasing NF-kappa-B transcriptional activity through promoting nuclear retention and phosphorylation of p65 [CS: 7]. The enhanced NF-kappa-B signaling aids in cellular survival and repair processes, countering the effects of the initial cardiac stress [CS: 7].

Furthermore, AKIP1's role in promoting cardiomyocyte growth via the Akt pathway is critical during cardiac stress [CS: 7]. In hypertrophic conditions, where the heart muscle enlarges to compensate for increased workload or damage, AKIP1's upregulation supports this adaptive growth [CS: 7]. By stimulating cardiomyocyte growth, AKIP1 assists in maintaining cardiac output and function, counteracting the detrimental effects of sustained stress, such as pressure overload or myocardial infarction [CS: 7].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: low tissue specificity [https://www.proteinatlas.org/ENSG00000166452/tissue]

Cell type enchanced: low cell type specificity [https://www.proteinatlas.org/ENSG00000166452/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

Compounds that decrease expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest

Most relevant biomarkers with lower score or lower probability of association with disease or organ of interest: