scholarly journals Aging Regulated Through a Stability Model of Insulin/Insulin Growth Factor Receptor Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Marc Tatar
Keyword(s):  
Growth Factor ◽  
Insulin Receptor ◽  
Tyrosine Kinases ◽  
Phosphorylation Site ◽  
Growth Factor Receptor ◽  
High Threshold ◽  
Insulin Growth Factor ◽  
Trade Offs ◽  
The Stability ◽  
New Research

Mutations of the insulin-like receptor in Drosophila extend lifespan. New research suggests this receptor operates in two modes. The first extends lifespan while slowing reproduction and reducing growth. The second strongly extends lifespan without impairing growth or reproduction; it confers longevity assurance. The mutation that confers longevity assurance resides in the kinase insert domain, which contains a potential SH2 binding site for substrate proteins. We apply a recent model for the function of receptor tyrosine kinases to propose how insulin receptor structure can modulate aging. This concept hypothesizes that strong insulin-like ligands promote phosphorylation of high threshold substrate binding sites to robustly induce reproduction, which impairs survival as a consequence of trade-offs. Lower levels of receptor stimulation provide less kinase dimer stability, which reduces reproduction and extends lifespan by avoiding reproductive costs. Environmental conditions that favor diapause alter the expression of insulin ligands to further repress the stability of the interacting kinase domains, block phosphorylation of low threshold substrates and thus induce a unique molecular program that confers longevity assurance. Mutations of the insulin receptor that block low-phosphorylation site interactions, such as within the kinase insert domain, can extend lifespan while maintaining overall dimer stability. These flies are long-lived while maintaining reproduction and growth. The kinase insert domain of Drosophila provides a novel avenue from which to seek signaling of the insulin/insulin-like growth factor system of humans that modulate aging without impacting reproduction and growth, or incurring insulin resistance pathology.

Insulin Receptor: 3D Reconstruction from Darkfield Stem Images, Structural Interpretation and Functional Model

1999 ◽  
Vol 5 (S2) ◽  
pp. 408-409
Author(s):  
F.P. Ottensmeyer ◽  
R.Z.-T. Luo ◽  
A.B. Fernandes ◽  
D. Benia ◽  
C.C. Yip
Keyword(s):  
Growth Factor ◽  
Insulin Receptor ◽  
Tyrosine Kinases ◽  
Quaternary Structure ◽  
Functional Model ◽  
Growth Factor Receptor ◽  
Insulin Binding ◽  
Dark Field ◽  
Bovine Insulin ◽  
Structural Basis

We have reconstructed the three-dimensional quaternary structure of the complete 480 kDa insulin receptor (IR), complexed with NanoGold-labelled insulin, via sets of electron micrographs obtained by low-dose low-temperature dark field scanning transmission electron microscopy (STEM).Insulin binding to IR in mammalian cell membranes is essential for its manifold effects such as glucose homeostasis, increased protein synthesis, growth, and development. IR belongs to the superfamily of transmembrane receptor tyrosine kinases that include the monomeric epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR). In contrast, IR and its homologues IGF-1R (insulin-like growth factor 1 receptor) and IRR (insulin receptorrelated receptor) are sub-types of this family that are intrinsic disulfide-linked dimers of two αβ heterodimers. Monomeric receptor TKs are inactive, but are activated by ligand-induced dimerization that results in autophosphorylation. IR-like TKs are also inactive even though they are already dimeric, and are activated by ligand binding without further oligomerization. Insulin binding to the extracellular domain of IR results in autophosphorylation of specific tyrosines to initiate an intracellular signal transduction cascade. However, because the quaternary structure of IR is not known, the structural basis for the mechanism of IR activation by extracellular insulin binding has not been elucidated.The insulin receptor was purified from human placenta. Bovine insulin was derivatized with NanoGold at the B chain Phel, a location not directly involved in receptor binding. Binding of derivatized insulin to the purified receptor was reduced only slightly compared to binding of the native insulin.

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 Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 184
Author(s):  
Kalpana K. Bhanumathy ◽  
Amrutha Balagopal ◽  
Frederick S. Vizeacoumar ◽  
Franco J. Vizeacoumar ◽  
Andrew Freywald ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinases ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Tyrosine Protein Kinase ◽  
Mesenchymal Epithelial Transition Factor ◽  
The Impact

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.

scholarly journals The Motile Breast Cancer Phenotype Roles of Proteoglycans/Glycosaminoglycans

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Dragana Nikitovic ◽  
Katerina Kouvidi ◽  
Kallirroi Voudouri ◽  
Aikaterini Berdiaki ◽  
Evgenia Karousou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Downstream Signaling ◽  
Insulin Growth Factor ◽  
Cancer Pathogenesis ◽  
Cellular Mediators ◽  
Epidermal Growth ◽  
Cancer Phenotype ◽  
Insulin Growth Factor Receptor

The consecutive stages of cancer growth and dissemination are obligatorily perpetrated through specific interactions of the tumor cells with their microenvironment. Importantly, cell-associated and tumor microenvironment glycosaminoglycans (GAGs)/proteoglycan (PG) content and distribution are markedly altered during tumor pathogenesis and progression. GAGs and PGs perform multiple functions in specific stages of the metastatic cascade due to their defined structure and ability to interact with both ligands and receptors regulating cancer pathogenesis. Thus, GAGs/PGs may modulate downstream signaling of key cellular mediators including insulin growth factor receptor (IGFR), epidermal growth factor receptor (EGFR), estrogen receptors (ERs), or Wnt members. In the present review we will focus on breast cancer motility in correlation with their GAG/PG content and critically discuss mechanisms involved. Furthermore, new approaches involving GAGs/PGs as potential prognostic/diagnostic markers or as therapeutic agents for cancer-related pathologies are being proposed.

scholarly journals Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors.

1996 ◽  
Vol 135 (6) ◽  
pp. 1633-1642 ◽  
Author(s):  
S Miyamoto ◽  
H Teramoto ◽  
J S Gutkind ◽  
K M Yamada
Keyword(s):  
Signal Transduction ◽  
Growth Factors ◽  
Growth Factor ◽  
Map Kinase ◽  
Tyrosine Kinases ◽  
Map Kinases ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Kinase Activation ◽  
Transient Activation

Integrins mediate cell adhesion, migration, and a variety of signal transduction events. These integrin actions can overlap or even synergize with those of growth factors. We examined for mechanisms of collaboration or synergy between integrins and growth factors involving MAP kinases, which regulate many cellular functions. In cooperation with integrins, the growth factors EGF, PDGF-BB, and basic FGF each produced a marked, transient activation of the ERK (extracellular signal-regulated kinase) class of MAP kinase, but only if the integrins were both aggregated and occupied by ligand. Transmembrane accumulation of total tyrosine-phosphorylated proteins, as well as nonsynergistic MAP kinase activation, could be induced by simple integrin aggregation, whereas enhanced transient accumulation of the EGF-receptor substrate eps8 required integrin aggregation and occupancy, as well as EGF treatment. Each type of growth factor receptor was itself induced to aggregate transiently by integrin ligand-coated beads in a process requiring both aggregation and occupancy of integrin receptors, but not the presence of growth factor ligand. Synergism was also observed between integrins and growth factors for triggering tyrosine phosphorylation of EGF, PDGF, and FGF receptors. This collaborative response also required both integrin aggregation and occupancy. These studies identify mechanisms in the signal transduction response to integrins and growth factors that require various combinations of integrin aggregation and ligands for integrin or growth factor receptors, providing opportunities for collaboration between these major regulatory systems.

Sign in / Sign up

Export Citation Format

Share Document