CRKL

Official Full Name

CRK like proto-oncogene, adaptor protein

Organism

Homo sapiens

GeneID

1399

Background

This gene encodes a protein kinase containing SH2 and SH3 (src homology) domains which has been shown to activate the RAS and JUN kinase signaling pathways and transform fibroblasts in a RAS-dependent fashion. It is a substrate of the BCR-ABL tyrosine kinase, plays a role in fibroblast transformation by BCR-ABL, and may be oncogenic.[provided by RefSeq, Jan 2009]

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Detailed Information

Recent Research Progress

The v-Crk avian sarcoma virus CT10 oncogene homolog-like (CRKL) is an adaptor protein consisting of an N-terminal Src homology 2 (SH2) domain followed by two SH3 domains. When its SH2 domain binds to the phosphorylated Y-x-x-P motif found in the docking protein, CRKL is activated, such as p130Cas, paxillin and GAB; the SH3N domain then mediates interaction with effector proteins by a proline-rich P-x-x-P-x-K motif. Overexpression of CRKL promotes anchorage-independent growth in Rat-1 fibroblasts and transforms human airway epithelial cells by activating the SOS1-RAS-RAF-ERK and Src-C3G-RAP1 pathways. It has been found that CRKL plays an important role in a variety of cancer mechanisms.

CRKL and endometrial carcinoma

Endometrial cancer is one of the most common gynecological cancers in the world. Although previous studies have reported that a variety of aberrantly expressed genes in endometrial cancer may lead to malignant behavior, there is still a strong need for new markers that can identify tumor progression and predict invasive phenotypes. Recent studies have found that CRKL is overexpressed in human endometrial cancer and is associated with advanced tumor grade. CRKL promotes tumor proliferation through regulation of cyclin proteins, and inhibits apoptosis through Bcl-2 and surviving up-regulation. CRKL can be used as a new therapeutic target for endometrial cancer.

CRKL and NSCLC

Anaplastic lymphoma kinase (ALK) gene rearrangement is a carcinogenic factor in a small number of patients with non-small cell lung cancer (NSCLC). CRKL tyrosine phosphorylation has been shown to be inhibited by pharmacological inhibition of ALK or knockdown of small interfering RNA (siRNA) in ALK rearranged cells. More importantly, knockdown of CRKL attenuated their cell proliferation, viability and migration, but it had no effect on ALK phosphorylation and expression in these cells. Furthermore, CRKL tyrosine phosphorylation was inhibited by dasatinib (an inhibitor of ABL and SRC kinases), which in combination with the ALK inhibitor crizotinib displayed a synergistic inhibitory effect in vitro. In conclusion, studies have shown that CRKL is a key downstream effector of ALK, and that combined inhibition of ALK and CRKL may represent an effective strategy for treating ALK-rearranged NSCLC patients.

CRKL and breast cancer

Breast cancer is one of the most common malignancies and seriously affects the health of women worldwide. Recent results indicated that CRKL was involved in the stromal cell-derived factor-1 (SDF-1) signaling pathway in breast cancer by maintaining a balance between the extracellular regulated protein kinases 1/2 (Erk1/2) and protein kinase B (Akt) pathways. Once this balance is broken, the Erk1/2 pathway will be blocked and the Akt pathway will increase, leading to inhibitory expression of MMP9. More importantly, dysfunction of the Erk1/2 and Akt pathways can influence the biology of breast cancer. Therefore, CRKL proteins or genes suggest important and interesting targets for breast cancer treatment.

CRKL and pancreatic cancer

Recent studies have shown that the expression of CRKL in pancreatic cancer specimens is higher than that in normal pancreatic tissue, and that CRKL can promote cell proliferation by promoting cell cycle. Cell cycle and invasion-associated molecular analysis revealed that CRKL up-regulated cyclin D1, cyclin A, matrix metalloproteinase 2 (MMP2) expression and phosphorylation of extracellular signal (ERK) regulatory kinase. In conclusion, related studies indicate that CRKL is overexpressed in human pancreatic cancer and promotes proliferation and invasion of pancreatic cancer cells through ERK signaling.

In conclusion, CRKL is required for the regulation of the malignant potential of human cancer, and there is increasing evidence that CRKL is involved in the carcinogenesis of solid tumors by regulating their biological behavior, including proliferation, differentiation and invasion. Therefore, further research on the role of CRKL in the mechanism of cancer development will provide new insights and new directions for the diagnosis and treatment of related cancers.

References:

Cai Le, et al. CRKL overexpression promotes cell proliferation and inhibits apoptosis in endometrial carcinoma. Oncology Letters, 2017, 13: 51-56
Lin Fu, et al. CRKL Promotes Lung Cancer Cell Invasion Through ERK-MMP9 Pathway. Molecular Carcinogenesis,2015, 54:E35–E44
Rong An, et al. CRKL mediates EML4-ALK signaling and is a potential therapeutic target for ALK-rearranged lung adenocarcinoma. Oncotarget, 2016, 7: 20
Lian Xin, et al. CrkL regulates SDF-1-induced breast cancer biology through balancing Erk1/2 and PI3K/Akt pathways. Med Oncol, 2015, 32:411
Abderrahim, et al. The role of CRKL in breast cancer metastasis: insights from systems biology. Syst Synth Biol, 2015, 9:141–146
Fu Lin, et al. CRKL protein overexpression enhances cell proliferation and invasion in pancreatic cancer. Tumor Biology, 2015, 36(2): 1015-1022

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