scholarly journals Quantitative Tyrosine Phosphoproteome Profiling of AXL Receptor Tyrosine Kinase Signaling Network

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4234
Author(s):  
Xinyan Wu ◽  
Li Wang ◽  
Nicole A. Pearson ◽  
Santosh Renuse ◽  
Ran Cheng ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Temporal Dynamics ◽  
Protein Tyrosine Phosphatases ◽  
Tyrosine Kinase Signaling ◽  
Rapid Induction ◽  
Solid Malignancies ◽  
Proteomics Approach ◽  
Axl Receptor Tyrosine Kinase

Overexpression and amplification of AXL receptor tyrosine kinase (RTK) has been found in several hematologic and solid malignancies. Activation of AXL can enhance tumor-promoting processes such as cancer cell proliferation, migration, invasion and survival. Despite the important role of AXL in cancer development, a deep and quantitative mapping of its temporal dynamic signaling transduction has not yet been reported. Here, we used a TMT labeling-based quantitative proteomics approach to characterize the temporal dynamics of the phosphotyrosine proteome induced by AXL activation. We identified >1100 phosphotyrosine sites and observed a widespread upregulation of tyrosine phosphorylation induced by GAS6 stimulation. We also detected several tyrosine sites whose phosphorylation levels were reduced upon AXL activation. Gene set enrichment-based pathway analysis indicated the activation of several cancer-promoting and cell migration/invasion-related signaling pathways, including RAS, EGFR, focal adhesion, VEGFR and cytoskeletal rearrangement pathways. We also observed a rapid induction of phosphorylation of protein tyrosine phosphatases, including PTPN11 and PTPRA, upon GAS6 stimulation. The novel molecules downstream of AXL identified in this study along with the detailed global quantitative map elucidating the temporal dynamics of AXL activation should not only help understand the oncogenic role of AXL, but also aid in developing therapeutic options to effectively target AXL.

scholarly journals The role of p21ras in receptor tyrosine kinase signaling

1995 ◽  
pp. 1-14
Author(s):  
J. L. Bos ◽  
B. M. T. Burgering ◽  
G. J. Pronk ◽  
A. M. M. de Vries-Smits ◽  
J. P. Medema ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Kinase Signaling ◽  
Tyrosine Kinase Signaling

Knockdown of AXL Receptor Tyrosine Kinase in Osteosarcoma Cells Leads to Decreased Proliferation and Increased Apoptosis

2013 ◽  
Vol 26 (1) ◽  
pp. 179-188 ◽  
Author(s):  
Y. Zhang ◽  
Y-J. Tang ◽  
Y. Man ◽  
F. Pan ◽  
Z-H. Li ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Distant Metastases ◽  
Tnm Staging ◽  
Loss Of Function ◽  
Ki 67 ◽  
Axl Receptor Tyrosine Kinase ◽  
Induced Apoptosis ◽  
And Function

Dysregulation of the Axl receptor tyrosine kinase (RTK) has been implicated in the development and progression of a variety of malignancies. Axl is known to activate strong anti-apoptotic signaling pathways that promote oncogenesis. However, the role of Axl plays in osteosarcoma (OS) remains elusive. The present study aimed to investigate the clinical significance and function of Axl in human OS. Forty cases of OS and corresponding adjacent non-cancerous tissues (ANCT) were collected. The expression of Axl was assessed using immunohistochemical assay through tissue microarray procedure. A loss-of-function experiment was performed to investigate the effects of small hairpin RNA (shRNA)-mediated knockdown of Axl on the expression of p-AKT, poly ADP-ribose polymerase (PARP) and Ki-67, the proliferative activities, indicated by MTT assay, and the apoptotic index in OS MG-63 cells. As a result, the expression of Axl was found in OS tissues with higher strong reactivity rate, compared with the ANCT (75.0% vs 20.0%, P=0.000), but it did not associate with the age, gender, tumor size, TNM staging and distant metastases (each P>0.05). Furthermore, knockdown of Axl inhibited the proliferative activities and induced apoptosis in MG-63 cells with decreased expression of p-AKT, and Ki-67 and increased expression of PARP. In conclusion, our findings suggest that Axl is highly expressed in most of the OS tissues compared with the ANCT, and knockdown of Axl inhibits proliferation and induces apoptosis of OS cells possibly through downregulation of the AKT pathway, suggesting that our findings may provide new insights into the potential therapeutic target for cancer.

scholarly journals AXL receptor tyrosine kinase: a possible therapeutic target in acute promyelocytic leukemia

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mariam Fatima ◽  
Salik Javed Kakar ◽  
Fazal Adnan ◽  
Khalid Khan ◽  
Afsar Ali Mian ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Tyrosine Kinase ◽  
Acute Promyelocytic Leukemia ◽  
Receptor Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Axl Receptor Tyrosine Kinase

Abstract Background Acute promyelocytic leukemia (APL) is a subset of acute myeloid leukemia (AML) which is characterized by the fusion of promyelocytic leukemia PML and retinoic acid receptor- alpha (RAR-alpha) genes. All-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) have resulted in durable cytogenetic and molecular remissions in most APL patients and have altered the natural history of the disease. Most APL patients treated with ATRA and/or ATO are now anticipated to have a nearly normal life expectancy. Unfortunately, relapse and resistance to the current treatment occur in APL patients and the outcome remains dismal in these refractory patients. AXL receptor tyrosine kinase (AXL-RTK) has been shown to increase tumour burden, provide resistance to therapy and is critical to maintain cancer stem cells (CSCs) in chronic myeloid leukemia (CML) by stabilizing β-catenin in the Wnt/β-catenin signalling pathway. However, the role of AXL-RTK has not been explored in PML/RARα-positive APL. This study aimed to explore the role of AXL-RTK receptor in PML/RARα-positive APL. Methods and results By using biochemical and pharmacological approaches, here we report that targeting of AXL-RTK is related to the down-regulation of β-catenin target genes including c-myc (p < 0.001), AXIN2 (p < 0.001), and HIF1α (p < 0.01) and induction of apoptosis in PML/RARα-positive APL cell line. Resistance to all-trans retinoic acid (ATRA) was also overcomed by targeting AXL-RTK with R428 in APL (p < 0.05). Conclusion Our results provide clear evidence of the involvement of AXL-RTK in leukemogenic potential of PML/RARα-positive APL and suggest targeting of AXL-RTK in the treatment of therapy resistant APL patients.

Sign in / Sign up

Export Citation Format

Share Document