Kofi
2011-10-27 07:21:32 UTC
A PTEN/beta-arrestin complex regulates the IGF-Ir pathway. In worms,
this clearly regulates lifespan, trading off growth and cellular
proliferation for cellular quality and impeded senescence. What's
interesting is how this is turning up in several pathways linked to
chronic disease.
Low-dose naltrexone tackles receptor desensitization caused by mu opioid
overstimulation via beta-arrestins. No doubt this research on tumor
suppressor PTEN will one day trace back to the opioid growth factor
pathway and low-dose naltrexone (LDN). Right now only the TLR9/mu
opioid connection appears immediately connected to the complex via the
IGF-1r partial agonist and innate antimicrobial, cathelicidin (LL-37).
Brief mu opioid agonism activates the IGF-I pathway (as does
cathelicidin, as a partial agonist). Prolonged mu opioid agonism
triggers desensitization and this happens to extend to the IGF-1r
pathway. Beta-arrestins aren't simply regulating one single receptor
that becomes too stimulated. Several of these pathways are crosslinked.
It's interesting how a growth signal, cathelicidin, is also a blanket
inhibitor of viruses, bacteria and other competing microorganisms.
FEBS Lett. 2010 Aug 20;584(16):3580-6. Epub 2010 Jul 17.
beta-Arrestin 2-mediated heterologous desensitization of IGF-IR by
prolonged exposure of SH-SY5Y neuroblastoma cells to a mu opioid agonist.
Sparta A, Baiula M, Campbell G, Spampinato S.
Department of Pharmacology, University of Bologna, Irnerio 48, 40126
Bologna, Italy.
Prolonged (12h) exposure of SH-SY5Y neuroblastoma cells to the mu-opioid
receptor (MOPr) agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin
(DAMGO) causes homologous desensitization as well as heterologous
desensitization of the extracellular signal-regulated kinase 1/2 (ERK
1/2) phosphorylation induced by insulin-like growth factor (IGF)-I.
Brief (15 min) but not prolonged exposure to DAMGO transregulates the
insulin-like growth factor-I (IGF-I) receptor, as evidenced by its
phosphorylation in the absence of IGF-I. Silencing of beta-arrestin 2
uncouples the crosstalk between the two receptors, thus maintaining
IGF-I-mediated receptor phosphorylation and ERK 1/2 activation even
after prolonged DAMGO exposure. Furthermore, MOPr-induced activation of
IGF-I receptor requires the tyrosine kinase c-Src. Copyright 2010
Federation of European Biochemical Societies. Published by Elsevier B.V.
All rights reserved.
Publication Types:
* Research Support, Non-U.S. Gov't
PMID: 20643133
EMBO J. 2011 Jun 3;30(13):2557-68.
Comment in:
* EMBO J. 2011;30(13):2513-5.
Distinct functional outputs of PTEN signalling are controlled by dynamic
association with beta-arrestins.
Lima-Fernandes E, Enslen H, Camand E, Kotelevets L, Boularan C, Achour
L, Benmerah A, Gibson LC, Baillie GS, Pitcher JA, Chastre E,
Etienne-Manneville S, Marullo S, Scott MG.
INSERM, U1016, Institut Cochin, Paris, France.
The tumour suppressor PTEN (phosphatase and tensin deleted on chromosome
10) regulates major cellular functions via lipid phosphatase-dependent
and -independent mechanisms. Despite its fundamental pathophysiological
importance, how PTEN's cellular activity is regulated has only been
partially elucidated. We report that the scaffolding proteins
beta-arrestins (beta-arrs) are important regulators of PTEN. Downstream
of receptor-activated RhoA/ROCK signalling, beta-arrs activate the lipid
phosphatase activity of PTEN to negatively regulate Akt and cell
proliferation. In contrast, following wound-induced RhoA activation,
beta-arrs inhibit the lipid phosphatase-independent anti-migratory
effects of PTEN. beta-arrs can thus differentially control distinct
functional outputs of PTEN important for cell proliferation and
migration.
Publication Types:
* Research Support, Non-U.S. Gov't
PMID: 21642958
Arrestins are multifunctional adaptor proteins best known for their role
in regulating G protein-coupled receptor signaling. Arrestins also
regulate other types of receptors, including the insulin-like growth
factor receptor (IGF-1R), although the mechanism by which this occurs is
not well understood. In Caenorhabditis elegans, the IGF-1R ortholog
DAF-2 regulates dauer formation, stress resistance, metabolism, and
lifespan through a conserved signaling cascade. To further elucidate the
role of arrestin in IGF-1R signaling, we employed an in vivo approach to
investigate the role of ARR-1, the sole arrestin ortholog in C. elegans,
on longevity. Here, we report that ARR-1 functions to positively
regulate DAF-2 signaling in C. elegans. arr-1 mutant animals exhibit
increased longevity and enhanced nuclear localization of DAF-16, an
indication of decreased DAF-2 signaling, whereas animals overexpressing
ARR-1 have decreased longevity. Genetic and biochemical analysis reveal
that ARR-1 functions to regulate DAF-2 signaling via direct interaction
with MPZ-1, a multi-PDZ domain-containing protein, via a C-terminal PDZ
binding domain in ARR-1. Interestingly, ARR-1 and MPZ-1 are found in a
complex with the phosphatase and tensin homolog (PTEN) ortholog DAF-18,
which normally serves as a suppressor of DAF-2 signaling, suggesting
that these three proteins work together to regulate DAF-2 signaling. Our
results suggest that the ARR-1-MPZ-1-DAF-18 complex functions to
regulate DAF-2 signaling in vivo and provide insight into a novel
mechanism by which arrestin is able to regulate IGF-1R signaling and
longevity [PMID 20207731]
Identification of the cathelicidin peptide LL-37 as agonist for the type
I insulin-like growth factor receptor (IGFr); The human cathelicidin
antimicrobial protein-18 and its C terminal peptide, LL-37, displays
broad antimicrobial activity that is mediated through direct contact
with the microbial cell membrane. In addition, recent studies reveal
that LL-37 is involved in diverse biological processes such as
immunomodulation, apoptosis, angiogenesis and wound healing. An
intriguing role for LL-37 in carcinogenesis is also beginning to emerge
and the aim of this paper was to explore if and how LL-37 contributes to
the signaling involved in tumor development. To this end, we
investigated the putative interaction between LL-37 and growth factor
receptors known to be involved in tumor growth and progression. Among
several receptors tested, LL-37 bound with the highest affinity to
insulin-like growth factor 1 receptor (IGF-1R), a receptor that is
strongly linked to malignant cellular transformation. Furthermore, this
interaction resulted in a dose-dependent phosphorylation and
ubiquitination of IGF-1R, with downstream signaling confined to the
mitogen-activated protein kinase/extracellular signal-regulated kinase
(MAPK/ERK)-pathway but not affecting phosphatidylinositol 3
kinase(PI3K)/Akt signaling. We found that signaling induced by LL-37 was
dependent on the recruitment of beta-arrestin to the fully functional
IGF-1R and by using mutant receptors we demonstrated that LL-37
signaling is dependent on beta-arrestin-1 binding to the C-terminus of
IGF-1R. When analyzing the biological consequences of increased ERK
activation induced by LL-37, we found that it resulted in enhanced
migration and invasion of malignant cells in an IGF-1R/beta-arrestin
manner, but did not affect cell proliferation. These results indicate
that LL-37 may act as a partial agonist for IGF-1R, with subsequent
intra-cellular signaling activation driven by the binding of
beta-arrestin-1 to the IGF-1R. Functional experiments show that
LL-37-dependent activation of the IGF-1R signaling resulted in increased
migratory and invasive potential of malignant cells [PMID 21685939]
RhoA/ROCK signaling -> beta-arrestins -> induce PTEN -> inhibit Akt/cell
proliferation; on the other hand: wounding -> RhoA -> beta-arrs ->
inhibits antimigratory effects of PTEN [PMID 21642958]
morphine -> TLR9 drop in astrocytes [PMID 21425908]; mu opioid -> TLR9
-> microglia apoptosis [PMID 21559519]; morphine interferes with the
TLR9/NFKB response in alveolar macrophages to S. pneumoniae; upregulates
TLR9 in conjuntion w/ M. tuberculosis [PMID 18292587]; methylated CpG ->
TLR9 -> cathelicidin (reduced colitis) [PMID 21762664]
Oncogene. 2008 Mar 6;27(11):1629-38. Epub 2007 Sep 10.
Picropodophyllin induces downregulation of the insulin-like growth
factor 1 receptor: potential mechanistic involvement of Mdm2 and
beta-arrestin1.
Vasilcanu R, Vasilcanu D, Rosengren L, Natalishvili N, Sehat B, Yin S,
Girnita A, Axelson M, Girnita L, Larsson O.
Department of Oncology and Pathology, Karolinska Institutet and
Karolinska University Hospital, Stockholm, Sweden.
The insulin-like growth factor 1 receptor (IGF-1R) is crucial for growth
and survival of malignant cells. Experience in targeting IGF-1R in
cancer models has shown that strategies promoting downregulation of the
receptor are much more efficient in inducing apoptosis than those
inhibiting the IGF-1R activity. Recently, we found that the cyclolignan
picropodophyllin (PPP) inhibits phosphorylation of IGF-1R and activation
of downstream signaling without interfering with the highly homologous
insulin receptor (IR). Furthermore, PPP treatment caused strong
regression of tumor grafts and prolonged survival of animals with
systemic tumor disease. Here we demonstrate that PPP also downregulates
the IGF-1R, whereas the IR and several other receptors were not
affected. PPP-induced IGF-1R downregulation required expression of the
MDM2 E3 ligase, which recently was found to ubiquitinate and cause
degradation of the IGF-1R. In addition knockdown of beta-arrestin1, the
adaptor molecule known to bridges MDM2 and IGF-1R, prevented
downregulation of the receptor and significantly decreased PPP-induced
cell death. All together these data suggest that PPP downregulates
IGF-1R by interfering with the action of beta-arrestin1/MDM2 as well as
the achieved receptor downregulation contributes to the apoptotic effect
of PPP.
Publication Types:
* Research Support, Non-U.S. Gov't
PMID: 17828296
Mol Cell Biol. 2002 Sep;22(17):6272-85.
Insulin induces heterologous desensitization of G-protein-coupled
receptor and insulin-like growth factor I signaling by downregulating
beta-arrestin-1.
Dalle S, Imamura T, Rose DW, Worrall DS, Ugi S, Hupfeld CJ, Olefsky JM.
Department of Medicine, Division of Endocrinology and Metabolism,
University of California, San Diego, La Jolla, California 92093-0673,
USA.
beta-Arrestin-1 mediates agonist-dependent desensitization and
internalization of G protein-coupled receptors (GPCRs) and is also
essential for GPCR mitogenic signaling. In addition, insulin-like growth
factor I receptor (IGF-IR) endocytosis is facilitated by
beta-arrestin-1, and internalization is necessary for IGF-I-stimulated
mitogen-activated protein (MAP) kinase activation. Here, we report that
treatment of cells for 12 h with insulin (100 ng/ml) induces an
approximately 50% decrease in cellular beta-arrestin-1 content due to
ubiquitination of beta-arrestin-1 and proteosome-mediated degradation.
This insulin-induced decrease in beta-arrestin-1 content was blocked by
inhibition of phosphatidylinositol-3 kinase (PI-3 kinase) and MEK with
wortmannin and PD98059, respectively. We also found a marked decrease in
the association of beta-arrestin-1 with the IGF-IR and a 55% inhibition
of IGF-I-stimulated MAP kinase phosphorylation. In insulin-treated,
beta-arrestin-1-downregulated cells, there was complete inhibition of
lysophosphatidic acid (LPA) or isoproterenol (ISO)-stimulated MAP kinase
phosphorylation. This was associated with a decrease in beta-arrestin-1
association with the beta2-AR as well as a decrease in
beta-arrestin-1-Src and Src-beta2-AR association. Ectopic expression of
wild-type beta-arrestin-1 in insulin-treated cells in which endogenous
beta-arrestin-1 had been downregulated rescued IGF-I- and LPA-stimulated
MAP kinase phosphorylation. In conclusion, we found the following. (i)
Chronic insulin treatment leads to enhanced beta-arrestin-1 degradation.
(ii) This downregulation of endogenous beta-arrestin-1 is associated
with decreased IGF-I-, LPA-, and ISO-mediated MAP kinase signaling,
which can be rescued by ectopic expression of wild-type beta-arrestin-1.
(iii) Finally, these results describe a novel mechanism for heterologous
desensitization, whereby insulin treatment can impair GPCR signaling,
and highlight the importance of beta-arrestin-1 as a target molecule for
this desensitization mechanism.
Publication Types:
* Research Support, Non-U.S. Gov't
* Research Support, U.S. Gov't, Non-P.H.S.
* Research Support, U.S. Gov't, P.H.S.
PMID: 12167719
this clearly regulates lifespan, trading off growth and cellular
proliferation for cellular quality and impeded senescence. What's
interesting is how this is turning up in several pathways linked to
chronic disease.
Low-dose naltrexone tackles receptor desensitization caused by mu opioid
overstimulation via beta-arrestins. No doubt this research on tumor
suppressor PTEN will one day trace back to the opioid growth factor
pathway and low-dose naltrexone (LDN). Right now only the TLR9/mu
opioid connection appears immediately connected to the complex via the
IGF-1r partial agonist and innate antimicrobial, cathelicidin (LL-37).
Brief mu opioid agonism activates the IGF-I pathway (as does
cathelicidin, as a partial agonist). Prolonged mu opioid agonism
triggers desensitization and this happens to extend to the IGF-1r
pathway. Beta-arrestins aren't simply regulating one single receptor
that becomes too stimulated. Several of these pathways are crosslinked.
It's interesting how a growth signal, cathelicidin, is also a blanket
inhibitor of viruses, bacteria and other competing microorganisms.
FEBS Lett. 2010 Aug 20;584(16):3580-6. Epub 2010 Jul 17.
beta-Arrestin 2-mediated heterologous desensitization of IGF-IR by
prolonged exposure of SH-SY5Y neuroblastoma cells to a mu opioid agonist.
Sparta A, Baiula M, Campbell G, Spampinato S.
Department of Pharmacology, University of Bologna, Irnerio 48, 40126
Bologna, Italy.
Prolonged (12h) exposure of SH-SY5Y neuroblastoma cells to the mu-opioid
receptor (MOPr) agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin
(DAMGO) causes homologous desensitization as well as heterologous
desensitization of the extracellular signal-regulated kinase 1/2 (ERK
1/2) phosphorylation induced by insulin-like growth factor (IGF)-I.
Brief (15 min) but not prolonged exposure to DAMGO transregulates the
insulin-like growth factor-I (IGF-I) receptor, as evidenced by its
phosphorylation in the absence of IGF-I. Silencing of beta-arrestin 2
uncouples the crosstalk between the two receptors, thus maintaining
IGF-I-mediated receptor phosphorylation and ERK 1/2 activation even
after prolonged DAMGO exposure. Furthermore, MOPr-induced activation of
IGF-I receptor requires the tyrosine kinase c-Src. Copyright 2010
Federation of European Biochemical Societies. Published by Elsevier B.V.
All rights reserved.
Publication Types:
* Research Support, Non-U.S. Gov't
PMID: 20643133
EMBO J. 2011 Jun 3;30(13):2557-68.
Comment in:
* EMBO J. 2011;30(13):2513-5.
Distinct functional outputs of PTEN signalling are controlled by dynamic
association with beta-arrestins.
Lima-Fernandes E, Enslen H, Camand E, Kotelevets L, Boularan C, Achour
L, Benmerah A, Gibson LC, Baillie GS, Pitcher JA, Chastre E,
Etienne-Manneville S, Marullo S, Scott MG.
INSERM, U1016, Institut Cochin, Paris, France.
The tumour suppressor PTEN (phosphatase and tensin deleted on chromosome
10) regulates major cellular functions via lipid phosphatase-dependent
and -independent mechanisms. Despite its fundamental pathophysiological
importance, how PTEN's cellular activity is regulated has only been
partially elucidated. We report that the scaffolding proteins
beta-arrestins (beta-arrs) are important regulators of PTEN. Downstream
of receptor-activated RhoA/ROCK signalling, beta-arrs activate the lipid
phosphatase activity of PTEN to negatively regulate Akt and cell
proliferation. In contrast, following wound-induced RhoA activation,
beta-arrs inhibit the lipid phosphatase-independent anti-migratory
effects of PTEN. beta-arrs can thus differentially control distinct
functional outputs of PTEN important for cell proliferation and
migration.
Publication Types:
* Research Support, Non-U.S. Gov't
PMID: 21642958
Arrestins are multifunctional adaptor proteins best known for their role
in regulating G protein-coupled receptor signaling. Arrestins also
regulate other types of receptors, including the insulin-like growth
factor receptor (IGF-1R), although the mechanism by which this occurs is
not well understood. In Caenorhabditis elegans, the IGF-1R ortholog
DAF-2 regulates dauer formation, stress resistance, metabolism, and
lifespan through a conserved signaling cascade. To further elucidate the
role of arrestin in IGF-1R signaling, we employed an in vivo approach to
investigate the role of ARR-1, the sole arrestin ortholog in C. elegans,
on longevity. Here, we report that ARR-1 functions to positively
regulate DAF-2 signaling in C. elegans. arr-1 mutant animals exhibit
increased longevity and enhanced nuclear localization of DAF-16, an
indication of decreased DAF-2 signaling, whereas animals overexpressing
ARR-1 have decreased longevity. Genetic and biochemical analysis reveal
that ARR-1 functions to regulate DAF-2 signaling via direct interaction
with MPZ-1, a multi-PDZ domain-containing protein, via a C-terminal PDZ
binding domain in ARR-1. Interestingly, ARR-1 and MPZ-1 are found in a
complex with the phosphatase and tensin homolog (PTEN) ortholog DAF-18,
which normally serves as a suppressor of DAF-2 signaling, suggesting
that these three proteins work together to regulate DAF-2 signaling. Our
results suggest that the ARR-1-MPZ-1-DAF-18 complex functions to
regulate DAF-2 signaling in vivo and provide insight into a novel
mechanism by which arrestin is able to regulate IGF-1R signaling and
longevity [PMID 20207731]
Identification of the cathelicidin peptide LL-37 as agonist for the type
I insulin-like growth factor receptor (IGFr); The human cathelicidin
antimicrobial protein-18 and its C terminal peptide, LL-37, displays
broad antimicrobial activity that is mediated through direct contact
with the microbial cell membrane. In addition, recent studies reveal
that LL-37 is involved in diverse biological processes such as
immunomodulation, apoptosis, angiogenesis and wound healing. An
intriguing role for LL-37 in carcinogenesis is also beginning to emerge
and the aim of this paper was to explore if and how LL-37 contributes to
the signaling involved in tumor development. To this end, we
investigated the putative interaction between LL-37 and growth factor
receptors known to be involved in tumor growth and progression. Among
several receptors tested, LL-37 bound with the highest affinity to
insulin-like growth factor 1 receptor (IGF-1R), a receptor that is
strongly linked to malignant cellular transformation. Furthermore, this
interaction resulted in a dose-dependent phosphorylation and
ubiquitination of IGF-1R, with downstream signaling confined to the
mitogen-activated protein kinase/extracellular signal-regulated kinase
(MAPK/ERK)-pathway but not affecting phosphatidylinositol 3
kinase(PI3K)/Akt signaling. We found that signaling induced by LL-37 was
dependent on the recruitment of beta-arrestin to the fully functional
IGF-1R and by using mutant receptors we demonstrated that LL-37
signaling is dependent on beta-arrestin-1 binding to the C-terminus of
IGF-1R. When analyzing the biological consequences of increased ERK
activation induced by LL-37, we found that it resulted in enhanced
migration and invasion of malignant cells in an IGF-1R/beta-arrestin
manner, but did not affect cell proliferation. These results indicate
that LL-37 may act as a partial agonist for IGF-1R, with subsequent
intra-cellular signaling activation driven by the binding of
beta-arrestin-1 to the IGF-1R. Functional experiments show that
LL-37-dependent activation of the IGF-1R signaling resulted in increased
migratory and invasive potential of malignant cells [PMID 21685939]
RhoA/ROCK signaling -> beta-arrestins -> induce PTEN -> inhibit Akt/cell
proliferation; on the other hand: wounding -> RhoA -> beta-arrs ->
inhibits antimigratory effects of PTEN [PMID 21642958]
morphine -> TLR9 drop in astrocytes [PMID 21425908]; mu opioid -> TLR9
-> microglia apoptosis [PMID 21559519]; morphine interferes with the
TLR9/NFKB response in alveolar macrophages to S. pneumoniae; upregulates
TLR9 in conjuntion w/ M. tuberculosis [PMID 18292587]; methylated CpG ->
TLR9 -> cathelicidin (reduced colitis) [PMID 21762664]
Oncogene. 2008 Mar 6;27(11):1629-38. Epub 2007 Sep 10.
Picropodophyllin induces downregulation of the insulin-like growth
factor 1 receptor: potential mechanistic involvement of Mdm2 and
beta-arrestin1.
Vasilcanu R, Vasilcanu D, Rosengren L, Natalishvili N, Sehat B, Yin S,
Girnita A, Axelson M, Girnita L, Larsson O.
Department of Oncology and Pathology, Karolinska Institutet and
Karolinska University Hospital, Stockholm, Sweden.
The insulin-like growth factor 1 receptor (IGF-1R) is crucial for growth
and survival of malignant cells. Experience in targeting IGF-1R in
cancer models has shown that strategies promoting downregulation of the
receptor are much more efficient in inducing apoptosis than those
inhibiting the IGF-1R activity. Recently, we found that the cyclolignan
picropodophyllin (PPP) inhibits phosphorylation of IGF-1R and activation
of downstream signaling without interfering with the highly homologous
insulin receptor (IR). Furthermore, PPP treatment caused strong
regression of tumor grafts and prolonged survival of animals with
systemic tumor disease. Here we demonstrate that PPP also downregulates
the IGF-1R, whereas the IR and several other receptors were not
affected. PPP-induced IGF-1R downregulation required expression of the
MDM2 E3 ligase, which recently was found to ubiquitinate and cause
degradation of the IGF-1R. In addition knockdown of beta-arrestin1, the
adaptor molecule known to bridges MDM2 and IGF-1R, prevented
downregulation of the receptor and significantly decreased PPP-induced
cell death. All together these data suggest that PPP downregulates
IGF-1R by interfering with the action of beta-arrestin1/MDM2 as well as
the achieved receptor downregulation contributes to the apoptotic effect
of PPP.
Publication Types:
* Research Support, Non-U.S. Gov't
PMID: 17828296
Mol Cell Biol. 2002 Sep;22(17):6272-85.
Insulin induces heterologous desensitization of G-protein-coupled
receptor and insulin-like growth factor I signaling by downregulating
beta-arrestin-1.
Dalle S, Imamura T, Rose DW, Worrall DS, Ugi S, Hupfeld CJ, Olefsky JM.
Department of Medicine, Division of Endocrinology and Metabolism,
University of California, San Diego, La Jolla, California 92093-0673,
USA.
beta-Arrestin-1 mediates agonist-dependent desensitization and
internalization of G protein-coupled receptors (GPCRs) and is also
essential for GPCR mitogenic signaling. In addition, insulin-like growth
factor I receptor (IGF-IR) endocytosis is facilitated by
beta-arrestin-1, and internalization is necessary for IGF-I-stimulated
mitogen-activated protein (MAP) kinase activation. Here, we report that
treatment of cells for 12 h with insulin (100 ng/ml) induces an
approximately 50% decrease in cellular beta-arrestin-1 content due to
ubiquitination of beta-arrestin-1 and proteosome-mediated degradation.
This insulin-induced decrease in beta-arrestin-1 content was blocked by
inhibition of phosphatidylinositol-3 kinase (PI-3 kinase) and MEK with
wortmannin and PD98059, respectively. We also found a marked decrease in
the association of beta-arrestin-1 with the IGF-IR and a 55% inhibition
of IGF-I-stimulated MAP kinase phosphorylation. In insulin-treated,
beta-arrestin-1-downregulated cells, there was complete inhibition of
lysophosphatidic acid (LPA) or isoproterenol (ISO)-stimulated MAP kinase
phosphorylation. This was associated with a decrease in beta-arrestin-1
association with the beta2-AR as well as a decrease in
beta-arrestin-1-Src and Src-beta2-AR association. Ectopic expression of
wild-type beta-arrestin-1 in insulin-treated cells in which endogenous
beta-arrestin-1 had been downregulated rescued IGF-I- and LPA-stimulated
MAP kinase phosphorylation. In conclusion, we found the following. (i)
Chronic insulin treatment leads to enhanced beta-arrestin-1 degradation.
(ii) This downregulation of endogenous beta-arrestin-1 is associated
with decreased IGF-I-, LPA-, and ISO-mediated MAP kinase signaling,
which can be rescued by ectopic expression of wild-type beta-arrestin-1.
(iii) Finally, these results describe a novel mechanism for heterologous
desensitization, whereby insulin treatment can impair GPCR signaling,
and highlight the importance of beta-arrestin-1 as a target molecule for
this desensitization mechanism.
Publication Types:
* Research Support, Non-U.S. Gov't
* Research Support, U.S. Gov't, Non-P.H.S.
* Research Support, U.S. Gov't, P.H.S.
PMID: 12167719