Akap12, also known as A-kinase anchoring protein 12 or Gravin, is a scaffolding protein. It plays a crucial role in compartmentalizing intracellular signaling pathways, such as those related to cAMP-dependent signaling by anchoring PKA. It is involved in various biological processes like controlling cytoskeletal architecture, maintaining endothelial integrity, and regulating glial function, and is important for forming blood-brain and blood-retinal barriers [3,5].

In heart-related studies, AKAP12OX mice (overexpressing cardiac Akap12) showed deteriorated systolic cardiac function, enlarged left ventricles, reduced contractility, and impaired calcium handling in response to isoproterenol, indicating that Akap12 upregulation accelerates cardiac dysfunction through the AKAP12-PDE8 axis [1]. In triple-negative breast cancer (TNBC), intratumoral AKAP12+ cancer-associated fibroblasts promote an immunosuppressive tumor microenvironment by mediating macrophage M2 polarization via the IL-34/CSF1R signaling, and a high population of these cells is correlated with poor prognosis [2]. In the context of liver injury, Akap12 deletion in mice activates the PI3K/AKT phosphorylation signaling pathway, increases PCSK6 and downstream inflammation-related genes, and promotes macrophage-derived inflammatory factors, suggesting Akap12 has a protective role in acute liver injury and chronic liver fibrosis [4]. For endothelial cells, Akap12 -/- mice had defective vascular plexus extension in the postnatal retina, and in cultured endothelial cells, Akap12 deficiency increased endothelial permeability along with ZO-1/Claudin 5 dysregulation and up-regulation/activation of the Rho kinase pathway [6,7].

In conclusion, Akap12 is essential for normal physiological functions, with its dysregulation contributing to various disease conditions. Studies using gene knockout or over-expression mouse models have revealed its role in cardiac dysfunction, TNBC, liver injury, and endothelial-related pathologies, providing insights into potential therapeutic targets for these diseases.

References:

1. Qasim, Hanan, Rajaei, Mehrdad, Xu, Ying, Wehrens, Xander H T, McConnell, Bradley K. 2024. AKAP12 Upregulation Associates With PDE8A to Accelerate Cardiac Dysfunction. In Circulation research, 134, 1006-1022. doi:10.1161/CIRCRESAHA.123.323655. https://pubmed.ncbi.nlm.nih.gov/38506047/

2. Liu, Zhenkun, Hu, Siyuan, Zhao, Xinlei, Weng, Jialei, Du, Yabing. 2024. AKAP12 positive fibroblast determines immunosuppressive contexture and immunotherapy response in patients with TNBC by promoting macrophage M2 polarization. In Journal for immunotherapy of cancer, 12, . doi:10.1136/jitc-2024-009877. https://pubmed.ncbi.nlm.nih.gov/39448199/

3. Qasim, Hanan, McConnell, Bradley K. 2020. AKAP12 Signaling Complex: Impacts of Compartmentalizing cAMP-Dependent Signaling Pathways in the Heart and Various Signaling Systems. In Journal of the American Heart Association, 9, e016615. doi:10.1161/JAHA.120.016615. https://pubmed.ncbi.nlm.nih.gov/32573313/

4. Wu, Xuan, Luo, Yuhong, Wang, Shan, Chen, Lei, Liu, Weiwei. 2022. AKAP12 ameliorates liver injury via targeting PI3K/AKT/PCSK6 pathway. In Redox biology, 53, 102328. doi:10.1016/j.redox.2022.102328. https://pubmed.ncbi.nlm.nih.gov/35576690/

5. Li, Hui. . Physiologic and pathophysiologic roles of AKAP12. In Science progress, 105, 368504221109212. doi:10.1177/00368504221109212. https://pubmed.ncbi.nlm.nih.gov/35775596/

6. Benz, Peter M, Ding, Yindi, Stingl, Heike, Popp, Rüdiger, Fleming, Ingrid. 2019. AKAP12 deficiency impairs VEGF-induced endothelial cell migration and sprouting. In Acta physiologica (Oxford, England), 228, e13325. doi:10.1111/apha.13325. https://pubmed.ncbi.nlm.nih.gov/31162891/

7. Seo, Ji Hae, Maki, Takakuni, Miyamoto, Nobukazu, Lo, Eng H, Arai, Ken. 2020. AKAP12 Supports Blood-Brain Barrier Integrity against Ischemic Stroke. In International journal of molecular sciences, 21, . doi:10.3390/ijms21239078. https://pubmed.ncbi.nlm.nih.gov/33260683/