Quantitative Tyrosine Phosphoproteome Profiling of AXL Receptor Tyrosine Kinase Signaling Network
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 cance...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/16/4234 |
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| author | Xinyan Wu Li Wang Nicole A. Pearson Santosh Renuse Ran Cheng Ye Liang Dong-Gi Mun Anil K. Madugundu Yaoyu Xu Parkash S. Gill Akhilesh Pandey |
| author_facet | Xinyan Wu Li Wang Nicole A. Pearson Santosh Renuse Ran Cheng Ye Liang Dong-Gi Mun Anil K. Madugundu Yaoyu Xu Parkash S. Gill Akhilesh Pandey |
| author_sort | Xinyan Wu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T08:56:16Z |
| format | Article |
| id | doaj.art-2685dccba6fd45df935d44abb95fb6b4 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T08:56:16Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2685dccba6fd45df935d44abb95fb6b42023-11-22T07:05:48ZengMDPI AGCancers2072-66942021-08-011316423410.3390/cancers13164234Quantitative Tyrosine Phosphoproteome Profiling of AXL Receptor Tyrosine Kinase Signaling NetworkXinyan Wu0Li Wang1Nicole A. Pearson2Santosh Renuse3Ran Cheng4Ye Liang5Dong-Gi Mun6Anil K. Madugundu7Yaoyu Xu8Parkash S. Gill9Akhilesh Pandey10Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USADepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USAMolecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USADepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USADepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USADepartment of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USADepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USADepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USADepartment of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USADepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USAOverexpression 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.https://www.mdpi.com/2072-6694/13/16/4234AXLGAS6receptor tyrosine kinaseprotein tyrosine phosphatasephosphorylationsignaling |
| spellingShingle | Xinyan Wu Li Wang Nicole A. Pearson Santosh Renuse Ran Cheng Ye Liang Dong-Gi Mun Anil K. Madugundu Yaoyu Xu Parkash S. Gill Akhilesh Pandey Quantitative Tyrosine Phosphoproteome Profiling of AXL Receptor Tyrosine Kinase Signaling Network Cancers AXL GAS6 receptor tyrosine kinase protein tyrosine phosphatase phosphorylation signaling |
| title | Quantitative Tyrosine Phosphoproteome Profiling of AXL Receptor Tyrosine Kinase Signaling Network |
| title_full | Quantitative Tyrosine Phosphoproteome Profiling of AXL Receptor Tyrosine Kinase Signaling Network |
| title_fullStr | Quantitative Tyrosine Phosphoproteome Profiling of AXL Receptor Tyrosine Kinase Signaling Network |
| title_full_unstemmed | Quantitative Tyrosine Phosphoproteome Profiling of AXL Receptor Tyrosine Kinase Signaling Network |
| title_short | Quantitative Tyrosine Phosphoproteome Profiling of AXL Receptor Tyrosine Kinase Signaling Network |
| title_sort | quantitative tyrosine phosphoproteome profiling of axl receptor tyrosine kinase signaling network |
| topic | AXL GAS6 receptor tyrosine kinase protein tyrosine phosphatase phosphorylation signaling |
| url | https://www.mdpi.com/2072-6694/13/16/4234 |
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