CASS4, also known as HEPL, is a member of the CAS (Crk-associated substrate) adaptor protein family [3]. These proteins lack enzymatic activity but contain specific sites for assembling signaling complexes crucial for cell proliferation, survival, migration, etc. All CAS family members act as intermediates in integrin-dependent signaling pathways at focal adhesions, associating with FAK and SRC family kinases to regulate the actin cytoskeleton [3].

Genome-wide association studies have implicated CASS4 as a risk gene for Alzheimer's disease (AD) [1,2,4]. In non-small cell lung cancer, overexpression of CASS4 promotes invasion by activating the AKT signaling pathway and inhibiting E-cadherin expression [5]. Also, in late-onset AD, a variant-to-function mapping study found that a regulatory element at the CASS4 locus influences microglial inflammatory capacity and DNA damage resolution, with evidence implicating RTFDC1 as a candidate effector gene [6]. Additionally, single-nucleotide polymorphisms in CASS4 have been associated with susceptibility to age-related cognitive decline [7], and CASS4, along with NEDD9 and PTK2B, may play roles in processes relevant to the pathogenesis of late-onset AD, such as hypoxia, vascular changes, inflammation, microtubule stabilization, and calcium signaling [8].

In conclusion, CASS4 is an important adaptor protein involved in multiple cellular signaling processes. Studies, especially those related to its association with diseases like Alzheimer's disease, age-related cognitive decline, and non-small cell lung cancer, highlight its significance in understanding disease pathogenesis. These disease-related associations of CASS4 provide valuable insights into potential therapeutic targets and disease mechanisms.

References:

1. Karch, Celeste M, Goate, Alison M. 2014. Alzheimer's disease risk genes and mechanisms of disease pathogenesis. In Biological psychiatry, 77, 43-51. doi:10.1016/j.biopsych.2014.05.006. https://pubmed.ncbi.nlm.nih.gov/24951455/

2. Schwartzentruber, Jeremy, Cooper, Sarah, Liu, Jimmy Z, Beltrao, Pedro, Bassett, Andrew. 2021. Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer's disease risk genes. In Nature genetics, 53, 392-402. doi:10.1038/s41588-020-00776-w. https://pubmed.ncbi.nlm.nih.gov/33589840/

3. Deneka, Alexander, Korobeynikov, Vladislav, Golemis, Erica A. 2015. Embryonal Fyn-associated substrate (EFS) and CASS4: The lesser-known CAS protein family members. In Gene, 570, 25-35. doi:10.1016/j.gene.2015.06.062. https://pubmed.ncbi.nlm.nih.gov/26119091/

4. Kim, Jong Hun. 2019. Genetics of Alzheimer's Disease. In Dementia and neurocognitive disorders, 17, 131-136. doi:10.12779/dnd.2018.17.4.131. https://pubmed.ncbi.nlm.nih.gov/30906402/

5. Li, Ailin, Zhang, Weiwei, Xia, Huifang, Qiu, Xueshan, Wang, Enhua. 2016. Overexpression of CASS4 promotes invasion in non-small cell lung cancer by activating the AKT signaling pathway and inhibiting E-cadherin expression. In Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 37, 15157-15164. doi:. https://pubmed.ncbi.nlm.nih.gov/27677288/

6. Burton, Elizabeth A, Argenziano, Mariana, Cook, Kieona, Grant, Struan F A, Chesi, Alessandra. 2024. Variant-to-function mapping of late-onset Alzheimer's disease GWAS signals in human microglial cell models implicates RTFDC1 at the CASS4 locus. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.08.22.609230. https://pubmed.ncbi.nlm.nih.gov/39229212/

7. Lin, Chieh-Hsin, Lin, Eugene, Lane, Hsien-Yuan. 2017. Genetic Biomarkers on Age-Related Cognitive Decline. In Frontiers in psychiatry, 8, 247. doi:10.3389/fpsyt.2017.00247. https://pubmed.ncbi.nlm.nih.gov/29209239/

8. Beck, Tim N, Nicolas, Emmanuelle, Kopp, Meghan C, Golemis, Erica A. 2014. Adaptors for disorders of the brain? The cancer signaling proteins NEDD9, CASS4, and PTK2B in Alzheimer's disease. In Oncoscience, 1, 486-503. doi:. https://pubmed.ncbi.nlm.nih.gov/25594051/