scholarly journals The Oncogenic Signaling Disruptor, NDRG1: Molecular and Cellular Mechanisms of Activity

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2382 ◽  
Author(s):  
Jason Chekmarev ◽  
Mahan Gholam Azad ◽  
Des R. Richardson
Keyword(s):  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Tumor Development ◽  
Pancreatic Tumors ◽  
Cellular Mechanisms ◽  
Oncogenic Signaling ◽  
Tumor Growth And Metastasis ◽  
B Lineage ◽  
Cbl Protein ◽  
Docking Protein

NDRG1 is an oncogenic signaling disruptor that plays a key role in multiple cancers, including aggressive pancreatic tumors. Recent studies have indicated a role for NDRG1 in the inhibition of multiple tyrosine kinases, including EGFR, c-Met, HER2 and HER3, etc. The mechanism of activity of NDRG1 remains unclear, but to impart some of its functions, NDRG1 binds directly to key effector molecules that play roles in tumor suppression, e.g., MIG6. More recent studies indicate that NDRG1s-inducing drugs, such as novel di-2-pyridylketone thiosemicarbazones, not only inhibit tumor growth and metastasis but also fibrous desmoplasia, which leads to chemotherapeutic resistance. The Casitas B-lineage lymphoma (c-Cbl) protein may be regulated by NDRG1, and is a crucial E3 ligase that regulates various protein tyrosine and receptor tyrosine kinases, primarily via ubiquitination. The c-Cbl protein can act as a tumor suppressor by promoting the degradation of receptor tyrosine kinases. In contrast, c-Cbl can also promote tumor development by acting as a docking protein to mediate the oncogenic c-Met/Crk/JNK and PI3K/AKT pathways. This review hypothesizes that NDRG1 could inhibit the oncogenic function of c-Cbl, which may be another mechanism of its tumor-suppressive effects.

Casitas B-lineage lymphoma mutants activate AKT to induce transformation in cooperation with class III receptor tyrosine kinases

2013 ◽  
Vol 41 (3) ◽  
pp. 271-280.e4 ◽  
Author(s):  
Harald Polzer ◽  
Hanna Janke ◽  
Diana Schmid ◽  
Wolfgang Hiddemann ◽  
Karsten Spiekermann
Keyword(s):  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Class Iii ◽  
B Lineage

Characterization of initial key steps of IL-17 receptor B oncogenic signaling for targeted therapy of pancreatic cancer

2021 ◽  
Vol 13 (583) ◽  
pp. eabc2823
Author(s):  
Heng-Hsiung Wu ◽  
Lung-Hung Tsai ◽  
Chun-Kai Huang ◽  
Pang-Hung Hsu ◽  
Mei-Yu Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Interleukin 17 ◽  
Oncogenic Signaling ◽  
Proinflammatory Gene ◽  
Tumor Growth And Metastasis ◽  
Key Steps ◽  
Proximal Signaling

The members of the interleukin-17 (IL-17) cytokine family and their receptors were identified decades ago. Unlike IL-17 receptor A (IL-17RA), which heterodimerizes with IL-17RB, IL-17RC, and IL-17RD and mediates proinflammatory gene expression, IL-17RB plays a distinct role in promoting tumor growth and metastasis upon stimulation with IL-17B. However, the molecular basis by which IL-17RB promotes oncogenesis is unknown. Here, we report that IL-17RB forms a homodimer and recruits mixed-lineage kinase 4 (MLK4), a dual kinase, to phosphorylate it at tyrosine-447 upon treatment with IL-17B in vitro. Higher amounts of phosphorylated IL-17RB in tumor specimens obtained from patients with pancreatic cancer correlated with worse prognosis. Phosphorylated IL-17RB recruits the ubiquitin ligase tripartite motif containing 56 to add lysine-63–linked ubiquitin chains to lysine-470 of IL-17RB, which further assembles NF-κB activator 1 (ACT1) and other factors to propagate downstream oncogenic signaling. Consequentially, IL-17RB mutants with substitution at either tyrosine-447 or lysine-470 lose their oncogenic activity. Treatment with a peptide consisting of amino acids 403 to 416 of IL-17RB blocks MLK4 binding, tyrosine-477 phosphorylation, and lysine-470 ubiquitination in vivo, thereby inhibiting tumorigenesis and metastasis and prolonging the life span of mice bearing pancreatic tumors. These results establish a clear pathway of how proximal signaling of IL-17RB occurs and provides insight into how this pathway provides a therapeutic target for pancreatic cancer.

scholarly journals Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia

2020 ◽  
Vol 21 (22) ◽  
pp. 8823
Author(s):  
Justin F. Creeden ◽  
Khaled Alganem ◽  
Ali S. Imami ◽  
Nicholas D. Henkel ◽  
F. Charles Brunicardi ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tyrosine Kinases ◽  
Tumor Development ◽  
Review Literature ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Desmoplastic Stroma ◽  
B Lymphoid ◽  
Therapeutic Research ◽  
Lymphocyte Cell

Kinase drug discovery represents an active area of therapeutic research, with previous pharmaceutical success improving patient outcomes across a wide variety of human diseases. In pancreatic ductal adenocarcinoma (PDAC), innovative pharmaceutical strategies such as kinase targeting have been unable to appreciably increase patient survival. This may be due, in part, to unchecked desmoplastic reactions to pancreatic tumors. Desmoplastic stroma enhances tumor development and progression while simultaneously restricting drug delivery to the tumor cells it protects. Emerging evidence indicates that many of the pathologic fibrotic processes directly or indirectly supporting desmoplasia may be driven by targetable protein tyrosine kinases such as Fyn-related kinase (FRK); B lymphoid kinase (BLK); hemopoietic cell kinase (HCK); ABL proto-oncogene 2 kinase (ABL2); discoidin domain receptor 1 kinase (DDR1); Lck/Yes-related novel kinase (LYN); ephrin receptor A8 kinase (EPHA8); FYN proto-oncogene kinase (FYN); lymphocyte cell-specific kinase (LCK); tec protein kinase (TEC). Herein, we review literature related to these kinases and posit signaling networks, mechanisms, and biochemical relationships by which this group may contribute to PDAC tumor growth and desmoplasia.

scholarly journals The Yin and Yang of Discoidin Domain Receptors (DDRs): Implications in Tumor Growth and Metastasis Development

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1725
Author(s):  
Sandra Majo ◽  
Patrick Auguste
Keyword(s):  
Tyrosine Kinases ◽  
Complex Structure ◽  
Tumor Development ◽  
Cancer Associated Fibroblasts ◽  
Metastasis Formation ◽  
Discoidin Domain Receptors ◽  
Metastasis Development ◽  
Yin And Yang ◽  
Tumor Growth And Metastasis ◽  
Main Components

The tumor microenvironment is a complex structure composed of the extracellular matrix (ECM) and nontumoral cells (notably cancer-associated fibroblasts (CAFs) and immune cells). Collagens are the main components of the ECM and they are extensively remodeled during tumor progression. Some collagens are ligands for the discoidin domain receptor tyrosine kinases, DDR1 and DDR2. DDRs are involved in different stages of tumor development and metastasis formation. In this review, we present the different roles of DDRs in these processes and discuss controversial findings. We conclude by describing emerging DDR inhibitory strategies, which could be used as new alternatives for the treatment of patients.

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