Stimulation by ghrelin of p42/p44 mitogen‐activated protein kinase through the GHS‐R1a receptor: Role of G‐proteins and β‐arrestins

Camiña, Jesús P.; Lodeiro, María F.; Ischenko, Olga; Martini, Ana Carolina; Casanueva, Felipe F.

doi:10.1002/jcp.21109

Cited by 58 publications

(52 citation statements)

References 73 publications

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“…It was not clear Rsk , Raf-1, PAK5, and 14-3-3 exist as complexes in some cell types (38,39,(47)(48)(49)(50). These complexes can regulate activity of some proteins acting through scaffold proteins (39,50,51). It is not yet known if B-Raf regulates NHE1 through part of a complex, although we did find that p90…”

Section: Discussionmentioning

confidence: 68%

B-Raf Associates with and Activates the NHE1 Isoform of the Na+/H+ Exchanger

Karki

Schrama

et al. 2011

Journal of Biological Chemistry

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The serine/threonine kinase B-Raf is the second most frequently occurring human oncogene after Ras. Mutations of B-Raf occur with the highest incidences in melanoma, and the most common mutant, V600E, renders B-Raf constitutively active. The sodium proton exchanger isoform 1 (NHE1) is a ubiquitously expressed plasma membrane protein responsible for regulating intracellular pH, cell volume, cell migration, and proliferation. A screen of protein kinases that bind to NHE1 revealed that B-Raf bound to the cytosolic regulatory tail of NHE1. Immunoprecipitation of NHE1 from HeLa and HEK cells confirmed the association of B-Raf with NHE1 in vivo. The expressed and purified C-terminal 182 amino acids of the NHE1 protein were also shown to associate with B-Raf protein in vitro. Because treatment with the kinase inhibitor sorafenib decreased NHE1 activity in HeLa and HEK cells, we examined the role of B-Raf in regulating NHE1 in malignant melanoma cells. Melanoma cells with the B-RafV600E mutation demonstrated increased resting intracellular pH that was dependent on elevated NHE1 activity. NHE1 activity after an acute acid load was also elevated in these cell lines. Moreover, inhibition of B-Raf activity by either sorafenib, PLX4720, or siRNA reduction of B-Raf levels abolished ERK phosphorylation and decreased NHE1 activity. These results demonstrate that B-Raf associates with and stimulates NHE1 activity and that B-Raf V600E also increases NHE1 activity that raises intracellular pH.

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Section: Discussionmentioning

confidence: 68%

B-Raf Associates with and Activates the NHE1 Isoform of the Na+/H+ Exchanger

Karki

Schrama

et al. 2011

Journal of Biological Chemistry

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“…However, like many other GPCRs (Gudermann et al, 1996;Wise et al, 1997), it is also able to modulate cellular signaling via pathways initiated via activation of other heterotrimeric G proteins (Holst et al, 2005;Camiñ a et al, 2007;Dezaki et al, 2007). When membranes of HEK293 cells transfected transiently to express both the ghrelin receptor and the G protein G␣ o1 were employed in […”

Section: Resultsmentioning

confidence: 99%

Growth Hormone Secretagogues and Growth Hormone Releasing Peptides Act As Orthosteric Super-Agonists but Not Allosteric Regulators for Activation of the G Protein Gαo1 by the Ghrelin Receptor

Bennett¹,

Langmead²,

Wise³

et al. 2009

Molecular Pharmacology

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Some growth hormone secretagogues act as agonists at the ghrelin receptor and have been described as "ago-allosteric" ligands because of an ability to also modulate the maximum efficacy and potency of ghrelin (Holst et al., 2005). In membranes prepared from cells coexpressing the human ghrelin receptor and, growth hormone-releasing peptide 6 (GHRP-6), and the 2(R)-hydroxypropyl derivative of 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo- -692,585) each functioned as direct agonists, and each displayed higher efficacy than ghrelin. The effect of multiple, fixed concentrations of each of these ligands on the function and concentration-dependence of ghrelin and the effect of multiple, fixed concentrations of ghrelin on the action of MK-677, GHRP-6, and L-692,585 was analyzed globally according to a modified version of an operational model of allosterism that accounts for allosteric modulation of affinity, efficacy, and allosteric agonism. Each of the data sets was best fit by a model of simple competition between a partial and a full agonist. Both positive and negative allosteric modulators are anticipated to alter the kinetics of binding of an orthosteric agonist. However, none of the proposed ago-allosteric regulators tested had any effect on the dissociation kinetics of 125 I-[His]-ghrelin, and GHRP-6 and MK-677 were able to fully displace 125 I-[His]-ghrelin from the receptor. At least in the system tested, each of the ligands acted in a simple competitive fashion with ghrelin as demonstrated by analysis according to a model whereby ghrelin is a partial agonist with respect to each of the synthetic agonists tested.

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“…Src activation through beta-arrestin and GPCR has been reported outside of photoreceptors [49, 50]. Immunohistochemistry has shown the presence of beta arrestins in photoreceptors [51].…”

Section: Discussionmentioning

confidence: 99%

Activation of oncogenic tyrosine kinase signaling promotes insulin receptor-mediated cone photoreceptor survival

2016

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In humans, daylight vision is primarily mediated by cone photoreceptors. These cells die in age-related retinal degenerations. Prolonging the life of cones for even one decade would have an enormous beneficial effect on usable vision in an aging population. Photoreceptors are postmitotic, but shed 10% of their outer segments daily, and must synthesize the membrane and protein equivalent of a proliferating cell each day. Although activation of oncogenic tyrosine kinase and inhibition of tyrosine phosphatase signaling is known to be essential for tumor progression, the cellular regulation of this signaling in postmitotic photoreceptor cells has not been studied. In the present study, we report that a novel G-protein coupled receptor–mediated insulin receptor (IR) signaling pathway is regulated by non-receptor tyrosine kinase Src through the inhibition of protein tyrosine phosphatase IB (PTP1B). We demonstrated the functional significance of this pathway through conditional deletion of IR and PTP1B in cones, in addition to delaying the death of cones in a mouse model of cone degeneration by activating the Src. This is the first study demonstrating the molecular mechanism of a novel signaling pathway in photoreceptor cells, which provides a window of opportunity to save the dying cones in retinal degenerative diseases.

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Stimulation by ghrelin of p42/p44 mitogen‐activated protein kinase through the GHS‐R1a receptor: Role of G‐proteins and β‐arrestins

Cited by 58 publications

References 73 publications

B-Raf Associates with and Activates the NHE1 Isoform of the Na+/H+ Exchanger

B-Raf Associates with and Activates the NHE1 Isoform of the Na+/H+ Exchanger

Growth Hormone Secretagogues and Growth Hormone Releasing Peptides Act As Orthosteric Super-Agonists but Not Allosteric Regulators for Activation of the G Protein Gαo1 by the Ghrelin Receptor

Activation of oncogenic tyrosine kinase signaling promotes insulin receptor-mediated cone photoreceptor survival

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