scholarly journals Macropinosomes as units of signal transduction

2018 ◽  
Vol 374 (1765) ◽  
pp. 20180157 ◽  
Author(s):  
Joel A. Swanson ◽  
Sei Yoshida
Keyword(s):  
Signal Transduction ◽  
Amino Acids ◽  
Growth Factor ◽  
Morphological Changes ◽  
Feedback Regulation ◽  
Phosphatidylinositol 3 Kinase ◽  
Cell Dimensions ◽  
Growth Factor Signalling ◽  
Dependent Growth ◽  
Biochemical Signals

Macropinosome formation occurs as a localized sequence of biochemical activities and associated morphological changes, which may be considered a form of signal transduction leading to the construction of an organelle. Macropinocytosis may also convey information about the availability of extracellular nutrients to intracellular regulators of metabolism. Consistent with this idea, activation of the metabolic regulator mechanistic target of rapamycin complex-1 (mTORC1) in response to acute stimulation by growth factors and extracellular amino acids requires internalization of amino acids by macropinocytosis. This suggests that macropinocytosis is necessary for mTORC1-dependent growth of metazoan cells, both as a route for delivery of amino acids to sensors associated with lysosomes and as a platform for growth factor-dependent signalling to mTORC1 via phosphatidylinositol 3-kinase (PI3K) and the Akt pathway. Because the biochemical signals required for the construction of macropinosomes are also required for cell growth, and inhibition of macropinocytosis inhibits growth factor signalling to mTORC1, we propose that signalling by growth factor receptors is organized into stochastic, structure-dependent cascades of chemical reactions that both build a macropinosome and stimulate mTORC1. More generally, as discrete units of signal transduction, macropinosomes may be subject to feedback regulation by metabolism and cell dimensions. This article is part of the Theo Murphy meeting issue ‘Macropinocytosis’.

Cracking the mild, difficult and fiendish codes within and downstream of the EGFR to link diagnostics and therapeutics

2007 ◽  
Vol 35 (1) ◽  
pp. 1-6 ◽  
Author(s):  
M. Waterfield
Keyword(s):  
Signal Transduction ◽  
Growth Factors ◽  
Growth Factor ◽  
Signalling Pathways ◽  
Growth Factor Signalling ◽  
Transduction Mechanisms

Over the last 45 years, I have been working on growth factors, their receptors and signal transduction mechanisms. This period has seen a tremendous growth in knowledge and technology, and all of this, together with a focus interest in oncology, has steered me along a path designed to understand growth factor signalling so that we can see how drugs that target signalling pathways might be able to control cancer. The knowledge that we already have is likely to lead to cures for many common cancers within the next 25 years.

scholarly journals Integration of the Extranuclear and Nuclear Actions of Estrogen

2005 ◽  
Vol 19 (8) ◽  
pp. 1951-1959 ◽  
Author(s):  
Ellis R. Levin
Keyword(s):  
Signal Transduction ◽  
Growth Factor ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Sex Steroid ◽  
Phosphatidylinositol 3 Kinase ◽  
Epidermal Growth ◽  
Small Pool ◽  
Physiological Outcomes ◽  
Nuclear Effects

Abstract Estrogen receptors (ERs) are localized to many sites within the cell, potentially contributing to overall estrogen action. In the nucleus, estrogen mainly modulates gene transcription, and the resulting protein products determine the cell biological actions of the sex steroid. In addition, a small pool of ERs localize to the plasma membrane and signal mainly though coupling, directly or indirectly, to G proteins. In response to steroid, signal transduction modulates both nontranscriptional and transcriptional events and impacts both the rapid and more prolonged actions of estrogen. Cross-talk from membrane-localized ERs to nuclear ERs can be mediated through growth factor receptor tyrosine kinases, such as epidermal growth factor receptor and IGF-I receptor. Growth factor receptors enact signal transduction to kinases such as ERK and phosphatidylinositol 3-kinase that phosphorylate and activate nuclear ERs, and this can also occur in the absence of sex steroid. A complex relationship between the membrane and nuclear effects of estrogen also involves membrane-initiated phosphorylation of coactivators, recruiting these proteins to the nuclear transcriptosome. Finally, large pools of cytoplasmic ERs exist, and some are localized to mitochondria. The integration of sex steroid effects at distinct cellular locations of its receptor leads to important cellular physiological outcomes and are manifest in both reproductive and nonreproductive organs.

scholarly journals Latent Membrane Protein 2A Inhibits Transforming Growth Factor-β1-Induced Apoptosis through the Phosphatidylinositol 3-Kinase/Akt Pathway

2004 ◽  
Vol 78 (4) ◽  
pp. 1697-1705 ◽  
Author(s):  
Makoto Fukuda ◽  
Richard Longnecker
Keyword(s):  
Signal Transduction ◽  
Growth Factor ◽  
Membrane Protein ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Latent Membrane Protein ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Latent Membrane Protein 2A ◽  
Tgf Β1

ABSTRACT Latent membrane protein 2A (LMP2A) blocks B-cell receptor signal transduction in vitro by binding the Syk and Lyn protein tyrosine kinases. As well as blocking B-cell signal transduction, LMP2A has been shown to activate the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, which acts as a survival signal in both B cells and epithelial cells. Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine that plays important roles in regulating cell growth and differentiation in many biological systems. The loss of the growth-inhibitory response to the TGF-β1 signal is found in many cancers and is widely thought to promote tumor development. In this study, we found that LMP2A induced the phosphorylation of Akt (serine 473) in Burkitt's lymphoma cell line Ramos and in gastric carcinoma cell line HSC-39 and partially enhanced cell viability following TGF-β1 treatment. In addition, LMP2A partially inhibited TGF-β1-induced DNA fragmentation and cleavage of poly(ADP-ribose) polymerase (PARP). In the presence of LY294002, an inhibitor of PI3-K, the LMP2A-mediated inhibitory effects on TGF-β1-induced DNA fragmentation and cleavage of PARP were alleviated. Furthermore, LMP2A did not alter the levels of expression of type I and type II TGF-β1 receptors. Taken together, these results suggest that LMP2A may inhibit TGF-β1-mediated apoptosis through activation of the PI3-K/Akt pathway.

scholarly journals Signal transduction by the hepatocyte growth factor receptor, c-met. Activation of the phosphatidylinositol 3-kinase.

1995 ◽  
Vol 5 (11) ◽  
pp. 1872-1881
Author(s):  
L G Cantley ◽  
L C Cantley
Keyword(s):  
Signal Transduction ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Intracellular Signaling ◽  
Growth Factor Receptor ◽  
Phosphatidylinositol 3 Kinase ◽  
Signaling Protein ◽  
Hepatocyte Growth Factor Receptor ◽  
Hepatocyte Growth ◽  
Phosphatidylinositol 3

Signal transduction by tyrosine kinase growth factor receptors involves the activation of multiple intracellular signaling pathways. In many cases, this occurs via direct binding of a downstream signaling protein to the phosphorylated receptor via src-homology 2 domains on the signaling protein. In this review of the hepatocyte growth factor receptor c-met, the ability of the amino acid sequence of the receptor to dictate which signaling proteins are activated is described, with particular emphasis on association with the phosphatidylinositol 3-kinase. Recent developments that provide new understanding of the mechanisms of downstream signal transduction by the phosphatidylinositol 3-kinase are discussed, including how these might be involved in the mitogenic, motogenic, and tubulogenic effects of hepatocyte growth factor on renal epithelial cells.

scholarly journals The origins and evolution of macropinocytosis

2018 ◽  
Vol 374 (1765) ◽  
pp. 20180158 ◽  
Author(s):  
Jason S. King ◽  
Robert R. Kay
Keyword(s):  
Growth Factor ◽  
Actin Polymerization ◽  
Common Ancestor ◽  
Growth Factor Receptor ◽  
Phosphatidylinositol 3 Kinase ◽  
Growth Factor Signalling ◽  
Core Components ◽  
The Common ◽  
Phagocytic Cups ◽  
Coupled Growth

In macropinocytosis, cells take up micrometre-sized droplets of medium into internal vesicles. These vesicles are acidified and fused to lysosomes, their contents digested and useful compounds extracted. Indigestible contents can be exocytosed. Macropinocytosis has been known for approaching 100 years and is described in both metazoa and amoebae, but not in plants or fungi. Its evolutionary origin goes back to at least the common ancestor of the amoebozoa and opisthokonts, with apparent secondary loss from fungi. The primary function of macropinocytosis in amoebae and some cancer cells is feeding, but the conserved processing pathway for macropinosomes, which involves shrinkage and the retrieval of membrane to the cell surface, has been adapted in immune cells for antigen presentation. Macropinocytic cups are large actin-driven processes, closely related to phagocytic cups and pseudopods and appear to be organized around a conserved signalling patch of PIP3, active Ras and active Rac that directs actin polymerization to its periphery. Patches can form spontaneously and must be sustained by excitable kinetics with strong cooperation from the actin cytoskeleton. Growth-factor signalling shares core components with macropinocytosis, based around phosphatidylinositol 3-kinase (PI3-kinase), and we suggest that it evolved to take control of ancient feeding structures through a coupled growth factor receptor. This article is part of the Theo Murphy meeting issue ‘Macropinocytosis’.

Necessity of tyrosine 719 and phosphatidylinositol 3′-kinase–mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the Asp814Val mutation

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 1094-1102 ◽  
Author(s):  
Koji Hashimoto ◽  
Itaru Matsumura ◽  
Tohru Tsujimura ◽  
Dae-Ki Kim ◽  
Hideki Ogihara ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Terminal Region ◽  
Acute Myelocytic Leukemia ◽  
Phosphatidylinositol 3 Kinase ◽  
Constitutive Activation ◽  
Kit Receptor ◽  
Dependent Growth ◽  
Phosphatidylinositol 3

Abstract Substitution of valine (Val) for aspartic acid (Asp) at codon 814 constitutively activates murine c-kit receptor tyrosine kinase (KIT), and Asp816Val mutation, corresponding to murine Asp814Val mutation, is found in patients with mastocytosis and acute myelocytic leukemia. However, the signal transduction pathways responsible for oncogenesis by the Asp814Val mutant (KITVal814) are not fully understood. To examine the oncogenic signal transduction of KITVal814, we converted 20 tyrosine (Tyr) residues to phenylalanine (Phe) in the cytoplasmic domain of KITVal814 or deleted the C-terminal region containing 2 other tyrosine residues (Del). Among various KITVal814- derived mutants, KITVal814-Tyr719Phe and KITVal814-Delseverely impaired receptor tyrosine phosphorylation and association with the p85 subunit of phosphatidylinositol 3′-kinase (p85PI3-K). Moreover, KITVal814-Tyr719Pheand KITVal814-Del failed to induce ligand-independent growth in Ba/F3 cells, indicating that Tyr719, the binding site for p85PI3-K, and the C-terminal region are indispensable for factor-independent growth by KITVal814. Although the C-terminal region was also required for ligand-dependent growth by wild-type KIT (KITWT), the Tyr719Phe substitution had negligible effects on ligand-dependent growth by KITWT. Furthermore, dominant-negative PI3-K significantly inhibited ligand-independent growth by KITVal814. These results demonstrate that Tyr719 is crucial for constitutive activation of KITVal814, but not for the ligand-induced activation of KITWT, and that the downstream signaling of PI3-K plays an important role in ligand-independent growth and tumorigenicity by KITVal814, thereby suggesting that KITVal814 is a unique activating mutation that leads to a distinguishable function from the effects of KITWT.

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