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Review
. 2024 Jan 30;22(1):77.
doi: 10.1186/s12964-024-01482-4.

The scaffold protein AXIN1: gene ontology, signal network, and physiological function

Lu Qiu #  1   2 , Yixuan Sun #  1 , Haoming Ning  1 , Guanyu Chen  1 , Wenshan Zhao  3 , Yanfeng Gao  4
Affiliations
Review

The scaffold protein AXIN1: gene ontology, signal network, and physiological function

Lu Qiu et al. Cell Commun Signal. .

Abstract

AXIN1, has been initially identified as a prominent antagonist within the WNT/β-catenin signaling pathway, and subsequently unveiled its integral involvement across a diverse spectrum of signaling cascades. These encompass the WNT/β-catenin, Hippo, TGFβ, AMPK, mTOR, MAPK, and antioxidant signaling pathways. The versatile engagement of AXIN1 underscores its pivotal role in the modulation of developmental biological signaling, maintenance of metabolic homeostasis, and coordination of cellular stress responses. The multifaceted functionalities of AXIN1 render it as a compelling candidate for targeted intervention in the realms of degenerative pathologies, systemic metabolic disorders, cancer therapeutics, and anti-aging strategies. This review provides an intricate exploration of the mechanisms governing mammalian AXIN1 gene expression and protein turnover since its initial discovery, while also elucidating its significance in the regulation of signaling pathways, tissue development, and carcinogenesis. Furthermore, we have introduced the innovative concept of the AXIN1-Associated Phosphokinase Complex (AAPC), where the scaffold protein AXIN1 assumes a pivotal role in orchestrating site-specific phosphorylation modifications through interactions with various phosphokinases and their respective substrates.

Keywords: AMPK signaling; AXIN1; AXIN1-associated phosphokinase complex (AAPC); Destruction complex; Hippo signaling; MAPK signaling; TGFβ signaling; Tumorigenesis; WNT/β-Catenin signaling; mTOR signaling.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The transcript and expression characteristics of the human AXIN1 gene. A Transcripts and exons of the AXIN1 gene. B The expression preference of five common transcripts of AXIN1 in multiple cancer types. (Data from Gene Expression Profiling Interactive Analysis: https://gepia2.cancer-pku.cn/)
Fig. 2
Fig. 2
Expression Profile of AXIN1 in Human Tissues. A Transcriptional expression levels of the AXIN1 gene in human tissues. The consensus dataset comprises normalized expression (nTPM) levels for 55 tissue types, created by integrating the HPA and GTEx transcriptomics datasets using an internal normalization pipeline. Color-coding is based on tissue groups, each consisting of tissues with shared functional features. B Expression of the AXIN1 protein in 44 human tissues. Color-coding is based on tissue groups, each consisting of tissues with functional features in common. C Summary of AXIN1 expression (nTPM) from all single cell types. Color-coding is based on cell type groups, each consisting of cell types with functional features in common. (Data from The Human Protein Atlas: https://www.proteinatlas.org/)
Fig. 3
Fig. 3
Regulation of AXIN1 expression. A Transcription factors regulating AXIN1 gene expression. Activating factors are denoted with a green background, while inhibitory factors are marked with a red background. B Micro-RNA regulators of AXIN1 mRNA. Grey boxes represent unverified targets. C Protein-level regulators of AXIN1. Proteins promoting AXIN1 stability are indicated with a green background, while proteins promoting AXIN1 degradation are marked with a red background
Fig. 4
Fig. 4
AXIN1 regulatory control on WNT/β-catenin Signaling. During WNT inactivity (WNT OFF), the homeostasis of β-catenin relies on the intricacies of the destruction complex, governing its proteasomal degradation through UPS pathway. Multiple factors, including FRAT1, PP1, PP2A, RIF1, SIRT4, and ZBED3, exert their influence on AXIN1 to inhibit the function of the destruction complex. Additionally, C9orf140, DAB2, TFEB, and WDR26 act on AXIN1 to facilitate the functioning of the destruction complex. When the WNT pathway is activated (WNT ON), AXIN1 is recruited to the WNTs-LRP5/6-FZDs-DVL complex, thereby relieving the suppression of the destruction complex on β-catenin. PAR2 serves to inhibit this process by acting on AXIN1, while γ-Pcdh-C3, SENP2, and SMURF1 also contribute to the inhibition of this process through interactions with AXIN1
Fig. 5
Fig. 5
AXIN1 regulatory control on Hippo and TGF-β Signaling. A Within the Hippo signaling cascade, the destruction complex undergoes phosphorylation catalyzed by LATS1/2, initiating a cascading series of post-translational modifications culminating in the ultimate degradation of YAP/TAZ. This process is facilitated through the UPS pathway. B In the context of TGF-β signaling, AXIN1 emerges as a pivotal actor, engaging directly with SMAD3/5/7. This interaction serves as the impetus for the degradation of SMAD proteins via the UPS pathway
Fig. 6
Fig. 6
AXIN1 regulatory control on AMPK and mTOR signaling pathways. In heightened energy states, mTORC1 activation unfolds at the lysosomal membrane via the engagement of the v-ATPase-Ragulator-RAGs complex. Concomitantly, an abundance of ATP exerts inhibitory effects, delicately modulating the assembly of the AXIN1-LKB1-AMPK complex and subsequently attenuating AMPK signaling. In contrast, under conditions of energy scarcity, AXIN1 undergoes recruitment to the lysosomal membrane through the v-ATPase-Ragulator complex. This orchestrated move directly quells mTORC1 signaling. Concurrently, elevated AMP levels stimulate the assembly of the AXIN1-LKB1-AMPK complex, thereby igniting AMPK signaling
Fig. 7
Fig. 7
Mutation statistics of the destruction complex members in the TCGA data. Mutation statistics of AXIN1 (A), AXIN2 (B), CTNNB1 (C), GSK3B (D), CNSK1A1 (E), APC (F) in the TCGA data using the TIMER platform. (Data from Tumor IMmune Estimation Resource: http://timer.cistrome.org/)
Fig. 8
Fig. 8
The scaffold protein AXIN1 as a promising pharmacological target
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