scholarly journals Activation and Inhibition of Anaplastic Lymphoma Kinase Receptor Tyrosine Kinase by Monoclonal Antibodies and Absence of Agonist Activity of Pleiotrophin

2005 ◽  
Vol 280 (28) ◽  
pp. 26039-26048 ◽  
Author(s):  
Christel Moog-Lutz ◽  
Joffrey Degoutin ◽  
Jean Y. Gouzi ◽  
Yvelyne Frobert ◽  
Nicole Brunet-de Carvalho ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Agonist Activity ◽  
Anaplastic Lymphoma

scholarly journals A crucial role for the Anaplastic lymphoma kinase receptor tyrosine kinase in gut development in Drosophila melanogaster

EMBO Reports ◽  
2003 ◽  
Vol 4 (8) ◽  
pp. 781-786 ◽  
Author(s):  
Christina E Lorén ◽  
Camilla Englund ◽  
Caroline Grabbe ◽  
Bengt Hallberg ◽  
Tony Hunter ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Crucial Role ◽  
Gut Development ◽  
Anaplastic Lymphoma

scholarly journals Anaplastic Lymphoma Kinase (ALK) Receptor Tyrosine Kinase: A Catalytic Receptor with Many Faces

2018 ◽  
Vol 19 (11) ◽  
pp. 3448 ◽  
Author(s):  
Hao Huang
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Fusion Proteins ◽  
Point Mutations ◽  
Clinical Applications ◽  
Significant Progress ◽  
Significant Information ◽  
Anaplastic Lymphoma ◽  
Membrane Bound

The anaplastic lymphoma kinase (ALK) receptor is a membrane-bound tyrosine kinase. The pathogenesis of several cancers is closely related to aberrant forms of ALK or aberrant ALK expression, including ALK fusion proteins, ALK-activated point mutations, and ALK amplification. Clinical applications of different ALK inhibitors represent significant progress in targeted therapy. Knowledge of different aspects of ALK biology can provide significant information to further the understanding of this receptor tyrosine kinase. In this mini-review, we briefly summarize different features of ALK. We also summarize some recent research advances on ALK fusion proteins in cancers.

Crystal structure of the ALK (anaplastic lymphoma kinase) catalytic domain

2010 ◽  
Vol 430 (3) ◽  
pp. 425-437 ◽  
Author(s):  
Christian C. Lee ◽  
Yong Jia ◽  
Nanxin Li ◽  
Xiuying Sun ◽  
Kenneth Ng ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Catalytic Domain ◽  
Peptide Binding ◽  
Kinase Domain ◽  
Full Length ◽  
Receptor Kinase ◽  
Anaplastic Lymphoma

ALK (anaplastic lymphoma kinase) is an RTK (receptor tyrosine kinase) of the IRK (insulin receptor kinase) superfamily, which share an YXXXYY autophosphorylation motif within their A-loops (activation loops). A common activation and regulatory mechanism is believed to exist for members of this superfamily typified by IRK and IGF1RK (insulin-like growth factor receptor kinase-1). Chromosomal translocations involving ALK were first identified in anaplastic large-cell lymphoma, a subtype of non-Hodgkin's lymphoma, where aberrant fusion of the ALK kinase domain with the NPM (nucleophosmin) dimerization domain results in autophosphosphorylation and ligand-independent activation. Activating mutations within the full-length ALK kinase domain, most commonly R1275Q and F1174L, which play a major role in neuroblastoma, were recently identified. To provide a structural framework for understanding these mutations and to guide structure-assisted drug discovery efforts, the X-ray crystal structure of the unphosphorylated ALK catalytic domain was determined in the apo, ADP- and staurosporine-bound forms. The structures reveal a partially inactive protein kinase conformation distinct from, and lacking, many of the negative regulatory features observed in inactive IGF1RK/IRK structures in their unphosphorylated forms. The A-loop adopts an inhibitory pose where a short proximal A-loop helix (αAL) packs against the αC helix and a novel N-terminal β-turn motif, whereas the distal portion obstructs part of the predicted peptide-binding region. The structure helps explain the reported unique peptide substrate specificity and the importance of phosphorylation of the first A-loop Tyr1278 for kinase activity and NPM–ALK transforming potential. A single amino acid difference in the ALK substrate peptide binding P−1 site (where the P-site is the phosphoacceptor site) was identified that, in conjunction with A-loop sequence variation including the RAS (Arg-Ala-Ser)-motif, rationalizes the difference in the A-loop tyrosine autophosphorylation preference between ALK and IGF1RK/IRK. Enzymatic analysis of recombinant R1275Q and F1174L ALK mutant catalytic domains confirms the enhanced activity and transforming potential of these mutants. The transforming ability of the full-length ALK mutants in soft agar colony growth assays corroborates these findings. The availability of a three-dimensional structure for ALK will facilitate future structure–function and rational drug design efforts targeting this receptor tyrosine kinase.

Targeting Small Molecule Tyrosine Kinases by Polyphenols: New Move Towards Anti-tumor Drug Discovery

2020 ◽  
Vol 17 (5) ◽  
pp. 585-615 ◽  
Author(s):  
Nikhil S. Sakle ◽  
Shweta A. More ◽  
Sachin A. Dhawale ◽  
Santosh N. Mokale
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Small Molecule ◽  
Anaplastic Lymphoma Kinase ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Myelogenous Leukemia ◽  
Cell Functions ◽  
Anaplastic Lymphoma

Background: Cancer is a complex disease involving genetic and epigenetic alteration that allows cells to escape normal homeostasis. Kinases play a crucial role in signaling pathways that regulate cell functions. Deregulation of kinases leads to a variety of pathological changes, activating cancer cell proliferation and metastases. The molecular mechanism of cancer is complex and the dysregulation of tyrosine kinases like Anaplastic Lymphoma Kinase (ALK), Bcr-Abl (Fusion gene found in patient with Chronic Myelogenous Leukemia (CML), JAK (Janus Activated Kinase), Src Family Kinases (SFKs), ALK (Anaplastic lymphoma Kinase), c-MET (Mesenchymal- Epithelial Transition), EGFR (Epidermal Growth Factor receptor), PDGFR (Platelet-Derived Growth Factor Receptor), RET (Rearranged during Transfection) and VEGFR (Vascular Endothelial Growth Factor Receptor) plays major role in the process of carcinogenesis. Recently, kinase inhibitors have overcome many problems of traditional cancer chemotherapy as they effectively separate out normal, non-cancer cells as well as rapidly multiplying cancer cells. Methods: Electronic databases were searched to explore the small molecule tyrosine kinases by polyphenols with the help of docking study (Glide-7.6 program interfaced with Maestro-v11.3 of Schrödinger 2017) to show the binding energies of polyphenols inhibitor with different tyrosine kinases in order to differentiate between the targets. Results: From the literature survey, it was observed that the number of polyphenols derived from natural sources alters the expression and signaling cascade of tyrosine kinase in various tumor models. Therefore, the development of polyphenols as a tyrosine kinase inhibitor against targeted proteins is regarded as an upcoming trend for chemoprevention. Conclusion: In this review, we have discussed the role of polyphenols as chemoreceptive which will help in future for the development and discovery of novel semisynthetic anticancer agents coupled with polyphenols.

scholarly journals NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner

2019 ◽  
Vol 11 (11) ◽  
pp. 994-1005 ◽  
Author(s):  
Ran Wei ◽  
Xuguang Liu ◽  
Courtney Voss ◽  
Wentao Qin ◽  
Lina Dagnino ◽  
...  
Keyword(s):  
Cell Fate ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Degradation Pathway ◽  
Anaplastic Lymphoma ◽  
Mechanistic Insight ◽  
Evolutionarily Conserved ◽  
Specific Manner ◽  
Insight Into

Abstract NUMB is an evolutionarily conserved protein that plays an important role in cell adhesion, migration, polarity, and cell fate determination. It has also been shown to play a role in the pathogenesis of certain cancers, although it remains controversial whether NUMB functions as an oncoprotein or tumor suppressor. Here, we show that NUMB binds to anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase aberrantly activated in several forms of cancer, and this interaction regulates the endocytosis and activity of ALK. Intriguingly, the function of the NUMB–ALK interaction is isoform-dependent. While both p66-NUMB and p72-NUMB isoforms are capable of mediating the endocytosis of ALK, the former directs ALK to the lysosomal degradation pathway, thus decreasing the overall ALK level and the downstream MAP kinase signal. In contrast, the p72-NUMB isoform promotes ALK recycling back to the plasma membrane, thereby maintaining the kinase in its active state. Our work sheds light on the controversial role of different isoforms of NUMB in tumorigenesis and provides mechanistic insight into ALK regulation.

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