scholarly journals The role of small adaptor proteins in the control of oncogenic signaling driven by tyrosine kinases in human cancer

Oncotarget ◽  
2016 ◽  
Vol 7 (10) ◽  
pp. 11033-11055 ◽  
Author(s):  
Cécile Naudin ◽  
Clément Chevalier ◽  
Serge Roche
Keyword(s):  
Tyrosine Kinases ◽  
Human Cancer ◽  
Adaptor Proteins ◽  
Oncogenic Signaling

scholarly journals Receptor Tyrosine Kinases in Kidney Development

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Renfang Song ◽  
Samir S. El-Dahr ◽  
Ihor V. Yosypiv
Keyword(s):  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Kidney Development ◽  
Receptor Tyrosine Kinases ◽  
Adaptor Proteins ◽  
Downstream Signaling ◽  
Arterial Blood ◽  
Intracellular Signal ◽  
Human Birth

The kidney plays a fundamental role in the regulation of arterial blood pressure and fluid/electrolyte homeostasis. As congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most common human birth defects, improved understanding of the cellular and molecular mechanisms that lead to CAKUT is critical. Accumulating evidence indicates that aberrant signaling via receptor tyrosine kinases (RTKs) is causally linked to CAKUT. Upon activation by their ligands, RTKs dimerize, undergo autophosphorylation on specific tyrosine residues, and interact with adaptor proteins to activate intracellular signal transduction pathways that regulate diverse cell behaviours such as cell proliferation, survival, and movement. Here, we review the current understanding of role of RTKs and their downstream signaling pathways in the pathogenesis of CAKUT.

scholarly journals IL1RAP potentiates multiple oncogenic signaling pathways in AML

2018 ◽  
Vol 215 (6) ◽  
pp. 1709-1727 ◽  
Author(s):  
Kelly Mitchell ◽  
Laura Barreyro ◽  
Tihomira I. Todorova ◽  
Samuel J. Taylor ◽  
Iléana Antony-Debré ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Interleukin 1 ◽  
Oncogenic Signaling ◽  
Genetic Deletion ◽  
Mechanistic Basis ◽  
Oncogenic Signaling Pathways ◽  
Receptor Accessory Protein

The surface molecule interleukin-1 receptor accessory protein (IL1RAP) is consistently overexpressed across multiple genetic subtypes of acute myeloid leukemia (AML) and other myeloid malignancies, including at the stem cell level, and is emerging as a novel therapeutic target. However, the cell-intrinsic functions of IL1RAP in AML cells are largely unknown. Here, we show that targeting of IL1RAP via RNA interference, genetic deletion, or antibodies inhibits AML pathogenesis in vitro and in vivo, without perturbing healthy hematopoietic function or viability. Furthermore, we found that the role of IL1RAP is not restricted to the IL-1 receptor pathway, but that IL1RAP physically interacts with and mediates signaling and pro-proliferative effects through FLT3 and c-KIT, two receptor tyrosine kinases with known key roles in AML pathogenesis. Our study provides a new mechanistic basis for the efficacy of IL1RAP targeting in AML and reveals a novel role for this protein in the pathogenesis of the disease.

Preliminary Studies on the Role of a Small GTPase, RhoA and Its Regulation in Imatinib Resistance

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4243-4243
Author(s):  
Song Zhang ◽  
Qingfeng Du ◽  
Hongqian Zhu ◽  
Rong Li ◽  
Zhi Liu ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Fusion Gene ◽  
Human Cancer ◽  
Chronic Phase ◽  
Small Gtpase ◽  
Signal Pathways ◽  
G1 Arrest ◽  
Imatinib Resistance ◽  
Point Mutant

Abstract Imatinib has impressive response rates and good tolerability quickly led to its adoption as frontline therapy for all patients with chronic-phase CML (chronic myeloid leukemia), but the therapeutic effect of imatinib is poor in the blast crisis, and imatinib resistance has become a major problem in CML. The possible mechanisms of imatinib resistance include the amplification of BCR-ABL fusion gene and its expression increase, the point mutant of BCR-ABL kinase domain and the effects of other tyrosine kinases such as Src, Hck and Lyn and so on. However, the second-generation tyrosine kinase inhibitors (such as nilotinib and dasatinib), which were developed to overcome imatinib resistance resulting from the point mutant or the activation of other tyrosine kinases, even can not prevent all patients with CML progression to drug resistance. So there would be the other potential factor in imatinib resistance. Our previous studies generated a new imatinib-resistant BCR/ABL-positive cell line, K562-R. The 50% inhibitory concentration of imatinib was 15-fold higher in K562-R than in the wild-type K562. The expression of RhoA gene is up-regulated in K562-R by microarray analyses. RhoA, a small GTPase (24KD), has been found overexpression in breast, colon, head and neck squamous cell carcinoma, bladderand testicular cancer, lung and gastric cancer. It plays an important role in the initiation as well as the progression of human cancer, but the potential role of RhoA related to imatinib resistance has yet been unknown. In this study, we firstly detect the biologic characteristic of K562-R cells with RhoA down-expression by RNA interference. When K562-R cells were transfected with 150nM siRNA-RhoA for 48 hours, the percentage of apoptotic K562-R cells is respectively 12.82% by AnnexinV-PI assay and 9.0% by Hoechst 33258 staining and both have significant increase, cell cycle analysis found significant G0/G1 arrest, the expression of CD29 increase and that of CD71 and GPA have no difference. Secondly, The K562-R cells were treated with three selective inhibitors, including PD98059 (Ras/MAPK inhibitor), LY294002 (PI3K/AKT inhibitor) and AG490(JAK/STAT inhibitor) for 2,4 and 8 hours and the expression of RhoA were analyzed by Western-Blotting. The expression of RhoA is arrested in the K562-R cells treated with PD98059 and AG490 and no different with LY294002. These results indicate that RhoA would be an important target in the down-stream of multi-signal pathways related to imatinib resistance and the potential function of RhoA in imatinib resistance involve in increasing of cell proliferation, resistance to cell apoptosis and changes of cell adhesion.

scholarly journals Control of Tyrosine Kinase Signalling by Small Adaptors in Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 669 ◽  
Author(s):  
Rudy Mevizou ◽  
Audrey Sirvent ◽  
Serge Roche
Keyword(s):  
Colorectal Cancer ◽  
Tyrosine Kinases ◽  
Human Cancer ◽  
Cell Communication ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Janus Kinase ◽  
Loss Of Function ◽  
Oncogenic Pathways ◽  
Tumour Formation

Tyrosine kinases (TKs) phosphorylate proteins on tyrosine residues as an intracellular signalling mechanism to coordinate intestinal epithelial cell communication and fate decision. Deregulation of their activity is ultimately connected with carcinogenesis. In colorectal cancer (CRC), it is still unclear how aberrant TK activities contribute to tumour formation because TK-encoding genes are not frequently mutated in this cancer. In vertebrates, several TKs are under the control of small adaptor proteins with potential important physiopathological roles. For instance, they can exert tumour suppressor functions in human cancer by targeting several components of the oncogenic TK signalling cascades. Here, we review how the Src-like adaptor protein (SLAP) and the suppressor of cytokine signalling (SOCS) adaptor proteins regulate the SRC and the Janus kinase (JAK) oncogenic pathways, respectively, and how their loss of function in the intestinal epithelium may influence tumour formation. We also discuss the potential therapeutic value of these adaptors in CRC.

The ErbB receptor tyrosine family as signal integrators.

2001 ◽  
pp. 151-159 ◽  
Author(s):  
N E Hynes ◽  
K Horsch ◽  
M A Olayioye ◽  
A Badache
Keyword(s):  
Tyrosine Kinases ◽  
Human Cancer ◽  
Membrane Receptors ◽  
Erbb Receptors ◽  
Erbb Receptor ◽  
Affinity Ligand ◽  
Biological Responses ◽  
High Affinity Ligand ◽  
Receptor Family

ErbB receptor tyrosine kinases (RTKs) and their ligands have important roles in normal development and in human cancer. Among the ErbB receptors only ErbB2 has no direct ligand; however, ErbB2 acts as a co-receptor for the other family members, promoting high affinity ligand binding and enhancement of ligand-induced biological responses. These characteristics demonstrate the central role of ErbB2 in the receptor family, which likely explains why it is involved in the development of many human malignancies, including breast cancer. ErbB RTKs also function as signal integrators, cross-regulating different classes of membrane receptors including receptors of the cytokine family. Cross-regulation of ErbB RTKs and cytokines receptors represents another mechanism for controlling and enhancing tumor cell proliferation.

scholarly journals Src family kinases, adaptor proteins and the actin cytoskeleton in epithelial-to-mesenchymal transition

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Maria A. Ortiz ◽  
Tatiana Mikhailova ◽  
Xiang Li ◽  
Baylee A. Porter ◽  
Alaji Bah ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Critical Role ◽  
Adaptor Proteins ◽  
Src Family Kinases ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Epithelial Homeostasis

AbstractOver a century of scientific inquiry since the discovery of v-SRC but still no final judgement on SRC function. However, a significant body of work has defined Src family kinases as key players in tumor progression, invasion and metastasis in human cancer. With the ever-growing evidence supporting the role of epithelial-mesenchymal transition (EMT) in invasion and metastasis, so does our understanding of the role SFKs play in mediating these processes. Here we describe some key mechanisms through which Src family kinases play critical role in epithelial homeostasis and how their function is essential for the propagation of invasive signals.

ACE2/Angiotensin-(1-7)/Mas Receptor Axis in Human Cancer: Potential Role for Pediatric Tumors

2020 ◽  
Vol 21 (9) ◽  
pp. 892-901 ◽  
Author(s):  
Ana Luiza Ataide Carneiro de Paula Gonzaga ◽  
Vitória Andrade Palmeira ◽  
Thomas Felipe Silva Ribeiro ◽  
Larissa Braga Costa ◽  
Karla Emília de Sá Rodrigues ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Angiotensin Ii ◽  
Pediatric Cancer ◽  
Pediatric Patients ◽  
Human Cancer ◽  
Experimental Studies ◽  
At1 Receptor ◽  
Pediatric Tumors ◽  
Mas Receptor

Background: Pediatric tumors remain the highest cause of death in developed countries. Research on novel therapeutic strategies with lesser side effects is of utmost importance. In this scenario, the role of Renin-Angiotensin System (RAS) axes, the classical one formed by angiotensinconverting enzyme (ACE), Angiotensin II and AT1 receptor and the alternative axis composed by ACE2, Angiotensin-(1-7) and Mas receptor, have been investigated in cancer. Objective: This review aimed to summarize the pathophysiological role of RAS in cancer, evidence for anti-tumor effects of ACE2/Angiotensin-(1-7)/Mas receptor axis and future therapeutic perspectives for pediatric cancer. Methods: Pubmed, Scopus and Scielo were searched in regard to RAS molecules in human cancer and pediatric patients. The search terms were “RAS”, “ACE”, “Angiotensin-(1-7)”, “ACE2”, “Angiotensin II”, “AT1 receptor”, “Mas receptor”, “Pediatric”, “Cancer”. Results: Experimental studies have shown that Angiotensin-(1-7) inhibits the growth of tumor cells and reduces local inflammation and angiogenesis in several types of cancer. Clinical trials with Angiotensin-( 1-7) or TXA127, a pharmaceutical grade formulation of the naturally occurring peptide, have reported promising findings, but not enough to recommend medical use in human cancer. In regard to pediatric cancer, only three articles that marginally investigated RAS components were found and none of them evaluated molecules of the alternative RAS axis. Conclusion: Despite the potential applicability of Angiotensin-(1-7) in pediatric tumors, the role of this molecule was never tested. Further clinical trials are necessary, also including pediatric patients, to confirm safety and efficiency and to define therapeutic targets.

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