The receptor tyrosine kinase AXL promotes migration and invasion in colorectal cancer

Uribe, Diana; Mandell, Edward K.; Watson, Adam W.; Martinez, Jesse D.; Leighton, Jonathan A.; Ghosh, Sourav; Rothlin, Carla V.

doi:10.1371/journal.pone.0179979

Cited by 40 publications

(33 citation statements)

References 49 publications

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“…6D, Proposed Model). One is governd by AXL which is activated by Gas6 (50), and can promote cell invasion and migration (31,32,47), cytoskeletal remodeling (51-53) and invadopodia formation and function (our results, Fig. 4).…”

Section: Examination Of Axl/ Erbb3 Expression Levels In Multiple Melamentioning

confidence: 55%

“…ERRB3 activation is up-regulated upon AXL suppression, leading to enhanced invadopodia function Given existing evidence that AXL promotes invasion and migration in a variety of cancer cells (30)(31)(32), together with our current findings, we hypothesized that an alternative invasionpromoting pathway may be activated following AXL inhibition by siRNA, leading to an elevation in invadopodia formation. Furthermore, this alternative pathway is not activated in instances of short-term inhibition of AXL ( Fig.…”

Section: Axl Is a Dual-function Regulator Of Invadopodia With Both Smentioning

confidence: 56%

“…In this comprehensive analysis, we found that the AXL receptor tyrosine kinase acts as a dual function regulator of invadopodia in both the A375 and 63T melanoma cell lines. AXL is known to be associated with an invasive phenotype in multiple cancers, including melanoma (26,27,47).…”

Section: Discussionmentioning

confidence: 99%

“…Testing the effect of siRNA KD of the A375 screen hits on 63T cells (see Supplementary Material 1), indicated that only the KD of FES, one of the 7 suppressive hits obtained with A375 cells, also induced a reduction in invadopodia function in 63T cells. Conversely, the 3 whose KD enhanced invadopodia in A375 cells (CSK, AXL and ABL2), had a similar effect on 63T cells (Table 2; AXL is a receptor tyrosine kinase, associated with an invasive phenotype in multiple cancers, including melanoma (26,27). In addition, AXL was shown to be involved in drug resistance mechanisms in melanoma and other cancers (28,29) Intrigued by the unexpected enhancement of invadopodia following the KD of AXL, and its novel association with invadopodia regulation, we chose to focus our study on the mechanism underlying the effect of this kinase on invadopodia formation and function.…”

Section: Primary Screen For Novel Invadopodia Regulators In Melanoma mentioning

confidence: 97%

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Cross-talk between the receptor tyrosine kinases AXL and ERBB3 regulates invadopodia formation in melanoma cells

Revach

Samuels

Geiger

2018

Preprint

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The invasive phenotype of metastatic cancer cells is accompanied by the formation of actin-rich invadopodia, which adhere to the extracellular matrix, and degrade it.In this study, we explored the role of the tyrosine kinome in the formation of invadopodia in metastatic melanoma cells. Using a microscopy-based siRNA screen, we identified novel invadopodia regulators, the knock-down of which either suppresses (e.g., TYK2, IGFR1, ERBB3, TYRO3, FES, ALK, PTK7) or enhances invadopodia formation and function (e.g., ABL2, AXL, CSK). Particularly intriguing was the discovery that the receptor tyrosine kinase AXL displays a dual regulatory function, manifested by enhancement of invadopodia function upon knock-down or long-term inhibition, as well as following its over-expression. We show here that this apparent contradiction may be attributed to the capacity of AXL to directly stimulate invadopodia; yet its suppression up-regulates the ERBB3 signaling pathway, which consequently activates core invadopodia regulators, and greatly enhances invadopodia function.Bioinformatic analysis of multiple melanoma cells points to an inverse expression pattern of AXL and ERBB3, with the apparent association of high-AXL melanomas, with high expression of invadopodia components and an invasive phenotype. The relevance of these results to melanoma metastasis in vivo, and to potential anti-invasion therapy, is discussed.

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Section: Examination Of Axl/ Erbb3 Expression Levels In Multiple Melamentioning

confidence: 55%

Section: Axl Is a Dual-function Regulator Of Invadopodia With Both Smentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Primary Screen For Novel Invadopodia Regulators In Melanoma mentioning

confidence: 97%

See 2 more Smart Citations

Cross-talk between the receptor tyrosine kinases AXL and ERBB3 regulates invadopodia formation in melanoma cells

Revach

Samuels

Geiger

2018

Preprint

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“…AXL is a receptor tyrosine kinase, associated with an invasive phenotype in multiple cancers, including melanoma (23,24). In addition, AXL was shown to be involved in drug resistance mechanisms in melanoma and other cancers (25).…”

Section: Primary Screen For Novel Invadopodia Regulators In Melanoma mentioning

confidence: 99%

Cross-Talk between Receptor Tyrosine Kinases AXL and ERBB3 Regulates Invadopodia Formation in Melanoma Cells

2019

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The invasive phenotype of metastatic cancer cells is accompanied by the formation of actin-rich invadopodia, which adhere to the extracellular matrix and degrade it. In this study, we explored the role of the tyrosine kinome in the formation of invadopodia in metastatic melanoma cells. Using a microscopy-based siRNA screen, we identified a series of regulators, the knockdown of which either suppresses (e.g., TYK2, IGFR1, ERBB3, TYRO3, FES, ALK, PTK7) or enhances (e.g., ABL2, AXL, CSK) invadopodia formation and function. Notably, the receptor tyrosine kinase AXL displayed a dual regulatory function, where both depletion or overexpression enhanced invadopodia formation and activity. This apparent contradiction was attributed to the capacity of AXL to directly stimulate invadopodia, yet its suppression upregulates the ERBB3 signaling pathway, which can also activate core invadopodia regulators and enhance invadopodia function. Bioinformatic analysis of multiple melanoma cell lines points to an inverse expression pattern of AXL and ERBB3. High expression of AXL in melanoma cells is associated with high expression of invadopodia components and an invasive phenotype. These results provide new insights into the complexity of metastasis-promoting mechanisms and suggest that targeting of multiple invadopodia signaling networks may serve as a potential anti-invasion therapy in melanoma.Significance: These findings uncover a unique interplay between AXL and ERBB3 in invadopodia regulation that points to the need for combined therapy in order to prevent invadopodia-mediated metastasis in melanoma.

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Receptor tyrosine kinases: biological functions and anticancer targeted therapy

Zhang,

2023

MedComm

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Receptor tyrosine kinases (RTKs) are a class of protein kinases that play crucial roles in various cellular processes, including cell migration, morphological differentiation, cell growth, and angiogenesis. In humans, 58 RTKs have been identified and categorized into 20 distinct families based on the composition of their extracellular regions. RTKs are primarily activated by specific ligands that bind to their extracellular region. They not only regulate tumor transformation, proliferation, metastasis, drug resistance, and angiogenesis, but also initiate and maintain the self‐renewal and cloning ability of cancer stem cells. Accurate diagnosis and grading of tumors with dysregulated RTKs are essential in clinical practice. There is a growing body of evidence supporting the benefits of RTKs‐targeted therapies for cancer patients, and researchers are actively exploring new targets and developing targeted agents. However, further optimization of RTK inhibitors is necessary to effectively target the diverse RTK alterations observed in human cancers. This review provides insights into the classification, structure, activation mechanisms, and expression of RTKs in tumors. It also highlights the research advances in RTKs targeted anticancer therapy and emphasizes their significance in optimizing cancer diagnosis and treatment strategies.

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The receptor tyrosine kinase AXL promotes migration and invasion in colorectal cancer

Cited by 40 publications

References 49 publications

Cross-talk between the receptor tyrosine kinases AXL and ERBB3 regulates invadopodia formation in melanoma cells

Cross-talk between the receptor tyrosine kinases AXL and ERBB3 regulates invadopodia formation in melanoma cells

Cross-Talk between Receptor Tyrosine Kinases AXL and ERBB3 Regulates Invadopodia Formation in Melanoma Cells

Receptor tyrosine kinases: biological functions and anticancer targeted therapy

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