Complexity of Receptor Tyrosine Kinase Signal Processing

Volinsky, Natalia; Kholodenko, Boris N.

doi:10.1101/cshperspect.a009043

Cited by 76 publications

(58 citation statements)

References 113 publications

(143 reference statements)

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“…Therefore, understanding the mechanisms by which this response is regulated is essential to identify therapeutic targets for neoplastic disorders. RNase L functions as an endogenous proliferative constraint (23)(24)(25)(26), and TTP is induced by mitogenic stimulation as a feedback mechanism to attenuate the proliferative response (76,90). In light of recent findings demonstrating the regulation of TTP mRNA by RNase L (23), and the interaction of RNase L and TTP proteins (45), we sought to investigate the RNase L-mediated regulation of TTP following mitogen stimulation that is relevant to their roles as antiproliferative effectors and to their mechanisms of action in the post-transcriptional control of target mRNA turnover.…”

Section: Discussionmentioning

confidence: 99%

RNase L Attenuates Mitogen-stimulated Gene Expression via Transcriptional and Post-transcriptional Mechanisms to Limit the Proliferative Response

Brennan-Laun

Ezelle

et al. 2014

Journal of Biological Chemistry

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Background: Serum-response factor (SRF) induces mRNAs that promote cell proliferation, whereas RNase L and tristetraprolin (TTP) degrade specific mRNAs to inhibit proliferation. Results: RNase L and TTP interact and down-regulate SRF to attenuate mitogen-induced gene expression. Conclusion: RNase L and TTP are components of a regulatory network that limits the proliferative response to mitogens. Significance: The RNase L/TTP axis represents a target to inhibit cancer cell proliferation.

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Section: Discussionmentioning

confidence: 99%

RNase L Attenuates Mitogen-stimulated Gene Expression via Transcriptional and Post-transcriptional Mechanisms to Limit the Proliferative Response

Brennan-Laun

Ezelle

et al. 2014

Journal of Biological Chemistry

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“…They reached relevant conclusions about the network structures and the relative activation strength of dimer pairs. The modeling of the network dynamics of the ErbB RTKs is discussed in detail in Volinsky and Kholodenko (2013).…”

Section: Behavior Of Intact Erbb Rtks In Live Cellsmentioning

confidence: 99%

Structure-Function Relationships of ErbB RTKs in the Plasma Membrane of Living Cells

Arndt‐Jovin¹,

Botelho²,

Jovin³

2014

Cold Spring Harbor Perspectives in Biology

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We review the states of the ErbB family of receptor tyrosine kinases (RTKs), primarily the EGF receptor (EGFR, ErbB1, HER1) and the orphan receptor ErbB2 as they exist in living mammalian cells, focusing on four main aspects: (1) aggregation state and distribution in the plasma membrane; (2) conformational features of the receptors situated in the plasma membrane, compared to the crystallographic structures of the isolated extracellular domains; (3) coupling of receptor disposition on filopodia with the transduction of signaling ligand gradients; and (4) ligand-independent receptor activation by application of a magnetic field.T his review deals exclusively with the disposition and function of the human ErbB (HER) family of receptor tyrosine kinases (RTKs) in the plasma membrane of living cells. We have divided the material into four main topics: (1) distribution and aggregation state of ErbB family members; (2) the 3D structure of the ErbB1 and ErbB2 receptors; (3) the role of receptors located on extensions (filopodia) of the cell body; and (4) the phenomenon and implications of nonligand-dependent activation of the receptors. DISTRIBUTION OF ErbB FAMILY MEMBERS IN THE PLASMA MEMBRANE OF LIVING CELLSThe association state(s) and activities of the ErbB family members in intact living cells differ widely depending on the expression level (number per cell) and the distribution (density, state of homo-and heteroassociation) of each receptor. There are numerous, highly contradictory views about the aggregation state of the receptors in the literature. During the last few years more accurate assessments of receptor distribution have been conducted on living rather than fixed cells. In the latter case, numerous artifacts account for important quantitative discrepancies. One example is the failure of formaldehyde fixation to prevent receptor redistribution (Brock et al. 1999;Tanaka et al. 2010). A more fundamental consideration relates to the hierarchical organization of the plasma membrane, extensively investigated and most recently reviewed by Kusumi et al. (2011). These investigators propose the existence of (1) a mesoscale (40 -300 nm) compartmentalization with actin cytoskeletal "fences" and transmembrane protein "pickets," (2) lipid raft domains (2 -

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“…The output of signaling networks, such as cascades, often feedback to stimulate or inhibit the processing of the input(s) of the network (Volinsky and Kholodenko, 2013). Negative feedback is a prerequisite for the emergence of oscillations.…”

Section: Negative Feedback In Signal Transduction Cascades: Oscillatimentioning

confidence: 99%

G Protein–Coupled Receptor Signaling Networks from a Systems Perspective

Roth¹,

Kholodenko²,

Smit³

et al. 2015

Mol Pharmacol

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The signal-transduction network of a mammalian cell integrates internal and external cues to initiate adaptive responses. Among the cell-surface receptors are the G protein-coupled receptors (GPCRs), which have remarkable signal-integrating capabilities. Binding of extracellular signals stabilizes intracellular-domain conformations that selectively activate intracellular proteins. Hereby, multiple signaling routes are activated simultaneously to degrees that are signal-combination dependent. Systems-biology studies indicate that signaling networks have emergent processing capabilities that go far beyond those of single proteins. Such networks are spatiotemporally organized and capable of gradual, oscillatory, all-or-none, and subpopulation-generating responses. Proteinprotein interactions, generating feedback and feedforward circuitry, are generally required for these spatiotemporal phenomena. Understanding of information processing by signaling networks therefore requires network theories in addition to biochemical and biophysical concepts. Here we review some of the key signaling systems behaviors that have been discovered recurrently across signaling networks. We emphasize the role of GPCRs, so far underappreciated receptors in systems-biology research.

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Complexity of Receptor Tyrosine Kinase Signal Processing

Cited by 76 publications

References 113 publications

RNase L Attenuates Mitogen-stimulated Gene Expression via Transcriptional and Post-transcriptional Mechanisms to Limit the Proliferative Response

RNase L Attenuates Mitogen-stimulated Gene Expression via Transcriptional and Post-transcriptional Mechanisms to Limit the Proliferative Response

Structure-Function Relationships of ErbB RTKs in the Plasma Membrane of Living Cells

G Protein–Coupled Receptor Signaling Networks from a Systems Perspective

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