E3 ligase–defective Cbl mutants lead to a generalized mastocytosis and myeloproliferative disease

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4197-4208 ◽  
Author(s):  
Srinivasa Rao Bandi ◽  
Christian Brandts ◽  
Marion Rensinghoff ◽  
Rebekka Grundler ◽  
Lara Tickenbrock ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Receptor Tyrosine Kinases ◽  
E3 Ligase ◽  
Myeloproliferative Disease ◽  
Primary Resistance ◽  
Murine Bone Marrow

Abstract Somatic mutations of Kit have been found in leukemias and gastrointestinal stromal tumors. The proto-oncogene c-Cbl negatively regulates Kit and Flt3 by its E3 ligase activity and acts as a scaffold. We recently identified the first c-Cbl mutation in human disease in an acute myeloid leukemia patient, called Cbl-R420Q. Here we analyzed the role of Cbl mutants on Kit-mediated transformation. Coexpression of Cbl-R420Q or Cbl-70Z with Kit induced cytokine-independent proliferation, survival, and clonogenic growth. Primary murine bone marrow retrovirally transduced with c-Cbl mutants and transplanted into mice led to a generalized mastocytosis, a myeloproliferative disease, and myeloid leukemia. Overexpression of these Cbl mutants inhibited stem cell factor (SCF)–induced ubiquitination and internalization of Kit. Both Cbl mutants enhanced the basal activation of Akt and prolonged the ligand-dependent activation. Importantly, transformation was observed also with kinase-dead forms of Kit and Flt3 in the presence of Cbl-70Z, but not in the absence of Kit or Flt3, suggesting a mechanism dependent on receptor tyrosine kinases, but independent of their kinase activity. Instead, transformation depends on the Src family kinase Fyn, as c-Cbl coimmunoprecipitated with Fyn and inhibition abolished transformation. These findings may explain primary resistance to tyrosine kinase inhibitors targeted at receptor tyrosine kinases.

Kinase Activity of RTKs Is Dispensable for Factor Independent Growth and Transformation of a Myeloid Cell Line 32D in the Presence of Cbl Mutants.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3970-3970
Author(s):  
◽  
Srinivasa Rao Bandi ◽  
Marion Rensinghoff ◽  
Rebekka Grundler ◽  
Lara Tickenbrock ◽  
...  
Keyword(s):  
Cell Line ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Myeloid Cell ◽  
Dominant Negative ◽  
Class Iii ◽  
Primary Resistance

Abstract Abstract 3970 Poster Board III-906 Purpose The Cbl proto-oncogene products have emerged as important components of the signal transduction cascades downstream of both non-receptor and receptor tyrosine kinases (RTKs). By regulation of receptor trafficking and degradation, they have been shown to tightly regulate the intensity and amplitude of RTK activation. c-Kit belongs to the family of the class-III RTKs and plays an important role in the pathogenesis of acute myeloid leukemia (AML). So far, very little is known about the role of c-Cbl mutants in the role of c-Kit signaling. Results We analyzed the interaction of c-Cbl with c-Kit and the functional relevance of this interaction in the IL-3-dependent murine myeloid progenitor cell line 32Dcl3. We recently identified the first c-Cbl mutation in human disease in an AML patient, named Cbl-R420Q. Co-expression of two different dominant negative mutants of c-Cbl (Cbl-R420Q or Cbl-70Z) with Kit induced cytokine-independent proliferation, survival and clonogenic growth. Importantly, transformation was observed also with kinase-dead forms of Kit and Flt3 in the presence of Cbl-70Z, but not in the absence of Kit or Flt3, suggesting a mechanism dependent on RTKs, but independent of their kinase activity. Instead, transformation appeared to depend on Src family kinases (SFKs), as c-Cbl co-immunoprecipitated with SFKs and SFK inhibition abolished transformation. Conclusion Our results indicate that c-Cbl has an important role in c-Kit signal mitigation. They demonstrate that disturbed mechanisms of c-Kit internalization have important implications for its transforming potential, possibly in the development of AML. Furthermore, these findings may explain primary resistance to tyrosine kinase inhibitors targeted at RTKs. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Recent Advances in the Role of Discoidin Domain Receptor Tyrosine Kinase 1 and Discoidin Domain Receptor Tyrosine Kinase 2 in Breast and Ovarian Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Li Chen ◽  
Xiangyi Kong ◽  
Yi Fang ◽  
Shishir Paunikar ◽  
Xiangyu Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tyrosine Kinase ◽  
Ligand Binding ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Receptor Tyrosine Kinases ◽  
Breast And Ovarian Cancer ◽  
Discoidin Domain Receptor

Discoidin domain receptor tyrosine kinases (DDRs) are a class of receptor tyrosine kinases (RTKs), and their dysregulation is associated with multiple diseases (including cancer, chronic inflammatory conditions, and fibrosis). The DDR family members (DDR1a-e and DDR2) are widely expressed, with predominant expression of DDR1 in epithelial cells and DDR2 in mesenchymal cells. Structurally, DDRs consist of three regions (an extracellular ligand binding domain, a transmembrane domain, and an intracellular region containing a kinase domain), with their kinase activity induced by receptor-specific ligand binding. Collagen binding to DDRs stimulates DDR phosphorylation activating kinase activity, signaling to MAPK, integrin, TGF-β, insulin receptor, and Notch signaling pathways. Abnormal DDR expression is detected in a range of solid tumors (including breast, ovarian, cervical liver, gastric, colorectal, lung, and brain). During tumorigenesis, abnormal activation of DDRs leads to invasion and metastasis, via dysregulation of cell adhesion, migration, proliferation, secretion of cytokines, and extracellular matrix remodeling. Differential expression or mutation of DDRs correlates with pathological classification, clinical characteristics, treatment response, and prognosis. Here, we discuss the discovery, structural characteristics, organizational distribution, and DDR-dependent signaling. Importantly, we highlight the key role of DDRs in the development and progression of breast and ovarian cancer.

scholarly journals Imatinib: A Breakthrough of Targeted Therapy in Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Nida Iqbal ◽  
Naveed Iqbal
Keyword(s):  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Cancer Therapies ◽  
Graft Versus Host ◽  
Oral Targeted Therapy

Deregulated protein tyrosine kinase activity is central to the pathogenesis of human cancers. Targeted therapy in the form of selective tyrosine kinase inhibitors (TKIs) has transformed the approach to management of various cancers and represents a therapeutic breakthrough. Imatinib was one of the first cancer therapies to show the potential for such targeted action. Imatinib, an oral targeted therapy, inhibits tyrosine kinases specifically BCR-ABL, c-KIT, and PDGFRA. Apart from its remarkable success in CML and GIST, Imatinib benefits various other tumors caused by Imatinib-specific abnormalities of PDGFR and c-KIT. Imatinib has also been proven to be effective in steroid-refractory chronic graft-versus-host disease because of its anti-PDGFR action. This paper is a comprehensive review of the role of Imatinib in oncology.

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 ◽  
Vol 7 (2) ◽  
pp. 205-211
Author(s):  
Kaynat Fatima ◽  
Syed Tasleem Raza ◽  
Ale Eba ◽  
Sanchita Srivastava ◽  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

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 Autoregulatory control of microtubule binding in doublecortin-like kinase 1

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Regina L Agulto ◽  
Melissa M Rogers ◽  
Tracy C Tan ◽  
Amrita Ramkumar ◽  
Ashlyn M Downing ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Therapeutic Target ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Binding Domain ◽  
Cancer Development ◽  
Microtubule Binding ◽  
Microtubule Binding Domain

The microtubule-associated protein, doublecortin-like kinase 1 (DCLK1), is highly expressed in a range of cancers and is a prominent therapeutic target for kinase inhibitors. The physiological roles of DCLK1 kinase activity and how it is regulated remain elusive. Here, we analyze the role of mammalian DCLK1 kinase activity in regulating microtubule binding. We find that DCLK1 autophosphorylates a residue within its C-terminal tail to restrict its kinase activity and prevent aberrant hyperphosphorylation within its microtubule-binding domain. Removal of the C-terminal tail or mutation of this residue causes an increase in phosphorylation within the doublecortin domains, which abolishes microtubule binding. Therefore, autophosphorylation at specific sites within DCLK1 have diametric effects on the molecule's association with microtubules. Our results suggest a mechanism by which DCLK1 modulates its kinase activity to tune its microtubule-binding affinity. These results provide molecular insights for future therapeutic efforts related to DCLK1's role in cancer development and progression.

scholarly journals Acute Myeloid Leukemia and Acute Promyelocytic Leukemia

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 82-101 ◽  
Author(s):  
Bob Löwenberg ◽  
James D. Griffin ◽  
Martin S. Tallman
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Promyelocytic Leukemia ◽  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Treatment Strategies ◽  
Promyelocytic Leukemia ◽  
Remission Induction ◽  
Novel Drugs ◽  
Acute Myeloid

Abstract The therapeutic approach to the patient with acute myeloid leukemia (AML) currently evolves toward new frontiers. This is particularly apparent from the entree of high-throughput diagnostic technologies and the identification of prognostic and therapeutic targets, the introduction of therapies in genetically defined subgroups of AML, as well as the influx of investigational approaches and novel drugs into the pipeline of clinical trials that target pathogenetic mechanisms of the disease. In Section I, Dr. Bob Löwenberg reviews current issues in the clinical practice of the management of adults with AML, including those of older age. Dr. Löwenberg describes upcoming possibilities for predicting prognosis in defined subsets by molecular markers and reviews experimental strategies to improve remission induction and postinduction treatment. In Section II, Dr. James Griffin reviews the mechanisms that lead to activation of tyrosine kinases by mutations in AML, the consequences of that activation for the cell, and the opportunities for targeted therapy and discusses some examples of developing novel drugs (tyrosine kinase inhibitors) and their effectiveness in AML (FLT3). In Section III, Dr. Martin Tallman describes the evaluation and management of patients with acute promyelocytic leukemia, a notable example of therapeutic progress in a molecularly defined entity of leukemia. Dr. Tallman focuses on the molecular genetics of APL, current curative treatment strategies and approaches for patients with relapsed and refractory disease. In addition, areas of controversy regarding treatment are addressed.

scholarly journals The C-terminus of CBFβ-SMMHC is required to induce embryonic hematopoietic defects and leukemogenesis

Blood ◽  
2013 ◽  
Vol 121 (4) ◽  
pp. 638-642 ◽  
Author(s):  
Yasuhiko Kamikubo ◽  
R. Katherine Hyde ◽  
Ling Zhao ◽  
Lemlem Alemu ◽  
Cecilia Rivas ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Myeloid Leukemia ◽  
Single Copy ◽  
Full Length ◽  
Myeloproliferative Disease ◽  
Chromosome 16 ◽  
C Terminus ◽  
Acute Myeloid

Abstract The C-terminus of CBFβ-SMMHC, the fusion protein produced by a chromosome 16 inversion in acute myeloid leukemia subtype M4Eo, contains domains for self-multimerization and transcriptional repression, both of which have been proposed to be important for leukemogenesis by CBFβ-SMMHC. To test the role of the fusion protein's C-terminus in vivo, we generated knock-in mice expressing a C-terminally truncated CBFβ-SMMHC (CBFβ-SMMHCΔC95). Embryos with a single copy of CBFβ-SMMHCΔC95 were viable and showed no defects in hematopoiesis, whereas embryos homozygous for the CBFβ-SMMHCΔC95 allele had hematopoietic defects and died in mid-gestation, similar to embryos with a single-copy of the full-length CBFβ-SMMHC. Importantly, unlike mice expressing full-length CBFβ-SMMHC, none of the mice expressing CBFβ-SMMHCΔC95 developed leukemia, even after treatment with a mutagen, although some of the older mice developed a nontransplantable myeloproliferative disease. Our data indicate that the CBFβ-SMMHC's C-terminus is essential to induce embryonic hematopoietic defects and leukemogenesis.

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