CRKL, also known as CT10 regulator of kinase-like, is a proto-oncogene encoding a SH2 and SH3 domain-containing adaptor protein. It is involved in multiple signaling pathways. For instance, it can regulate cell growth, differentiation, and migration by participating in pathways like PI3K/Akt, JNK/JUN, and the Hippo pathway [2,3,4]. CRKL's dysregulation has been associated with various diseases, especially cancers [2]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable tools for studying its functions.

In hepatocellular carcinoma (HCC), CRKL overexpression nullifies anti-PD-1 treatment efficacy. CRKL promotes the infiltration of tumor-associated neutrophils (TANs), which block CD8+ T cell infiltration and function. Mechanistically, CRKL inhibits APC-mediated proteasomal degradation of β-catenin, promoting VEGFα and CXCL1 expression. Targeting CRKL using CRISPR-Cas9 gene editing restores the efficacy of anti-PD-1 therapy in orthotopic mouse models and patient-derived organotypic tumor spheroid models [1]. In other cancer types, gene knockdown and knockout of Crk and CrkL in tumor cell lines suppress tumor cell functions like proliferation, migration, and invasion [2]. In lung adenocarcinoma, depletion of CRKL blunts Hh-GLI2 pathway-mediated cell proliferation and invasion, and CRKL knockout cells are more sensitive to EGFR-TKI and chemotherapeutics [5]. In cervical cancer, knocking down CRKL led to reduced cell proliferation and regulated alternative splicing of cancer-related genes [6].

In conclusion, CRKL plays a crucial role in multiple biological processes, especially in cancer development and progression. Studies using KO/CKO mouse models and other loss-of-function experiments have significantly contributed to understanding its role in diseases like HCC, colorectal cancer, lung adenocarcinoma, and cervical cancer. These findings suggest that CRKL could be a potential therapeutic target for treating related diseases.

References:

1. Xie, Peiyi, Yu, Mincheng, Zhang, Bo, Guo, Lei, Li, Hui. 2024. CRKL dictates anti-PD-1 resistance by mediating tumor-associated neutrophil infiltration in hepatocellular carcinoma. In Journal of hepatology, 81, 93-107. doi:10.1016/j.jhep.2024.02.009. https://pubmed.ncbi.nlm.nih.gov/38403027/

2. Park, Taeju. 2021. Crk and CrkL as Therapeutic Targets for Cancer Treatment. In Cells, 10, . doi:10.3390/cells10040739. https://pubmed.ncbi.nlm.nih.gov/33801580/

3. Wesener, Marie C, Weiler, Sofia M E, Bissinger, Michaela, Schirmacher, Peter, Breuhahn, Kai. 2024. CRKL Enhances YAP Signaling through Binding and JNK/JUN Pathway Activation in Liver Cancer. In International journal of molecular sciences, 25, . doi:10.3390/ijms25158549. https://pubmed.ncbi.nlm.nih.gov/39126118/

4. Guo, Chunmei, Gao, Chao, Lv, Xinxin, Liu, Shuqing, Sun, Ming-Zhong. 2021. CRKL promotes hepatocarcinoma through enhancing glucose metabolism of cancer cells via activating PI3K/Akt. In Journal of cellular and molecular medicine, 25, 2714-2724. doi:10.1111/jcmm.16303. https://pubmed.ncbi.nlm.nih.gov/33523562/

5. Liu, Xiaoming, Hu, Yan, Yu, Bentong, Peng, Kai, Gan, Xin. 2021. CRKL is a critical target of Hh-GLI2 pathway in lung adenocarcinoma. In Journal of cellular and molecular medicine, 25, 6280-6288. doi:10.1111/jcmm.16592. https://pubmed.ncbi.nlm.nih.gov/34076957/

6. Song, Qingling, Yi, Fengtao, Zhang, Yuhong, Yu, Han, Zhang, Yi. 2019. CRKL regulates alternative splicing of cancer-related genes in cervical cancer samples and HeLa cell. In BMC cancer, 19, 499. doi:10.1186/s12885-019-5671-8. https://pubmed.ncbi.nlm.nih.gov/31133010/