Regulation of insulin-like growth factor-1 receptor expression and signaling
Author: Vasilcanu, Radu
Date: 2007-06-15
Location: Cancer Centrum Karolinskas föreläsningssalen, R8:00, Karolinska Universitetssjukhuset, Stockholm
Time: 09.00
Department: Institutionen för onkologi-patologi / Department of Oncology-Pathology
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thesis.pdf (844.3Kb)
Abstract
Insulin-like growth factor-1 receptor (IGF-1R), a member of the insulin
receptor tyrosine kinase family is a broadly expressed transmembrane
receptor that plays a key role in malignant cell growth. IGF-1R transmits
information provided by extracellular stimuli into intracellular
signaling pathways resulting in the subsequent regulation of various
effector systems. Under normal cellular conditions IGF-1R signaling
network is tightly regulated. The most prominent regulator of IGF-1R
signal termination is desensitization of receptors by the removal of
activated receptors from the cell surface mediated by accelerated
endocytosis. For some membrane receptors the signal mediating receptor
internalization/downregulation is constituted by ubiquitination.
Recently, we showed that IGF-1R undergoes ubiquitination following ligand
stimulation. The proto-oncogene MDM2 was identified as an E3 ligase
involved in IGF-1R ubiquitination.
Studies on new events involved in IGF-1R downregulation and intracellular
signaling constitute the subject of the present thesis.
â-arrestins are ubiquitously expressed cytosolic proteins generally known
to be involved in the regulation of endocytosis and signaling elicited by
G protein-coupled receptors (GCPRs). We provide evidence that the two
widely co-expressed isoforms of â-arrestin, bind to the IGF-1R and, by
serving as adaptor proteins bring the oncoprotein E3 ligase MDM2 to the
receptor. Thus, â-arrestins promote ubiquitination but also degradation
of the receptor. In this respect, â-arrestin 1 is more potent then
isoform 2. Actually, â-arrestins are an absolute requirement for
interaction between MDM2 and IGF-1R, indicating their relevance for cell
growth and cancer.
We also investigated the role of â-arrestin 1 and MDM2 in intracellular
signaling. We found that both MDM2 and â-arrestin 1 also are necessary
for IGF-1 stimulated phosphorylation of ERK1/2 but not of Akt. In
addition, the modulating effect of MDM2 and â-arrestin 1 on ERK
activation has consequences on cell cycle progression. Thus, MDM2 and
â-arrestin 1 do not only induce ubiquitination and degradation of IGF-1R
but also influence cell growth by modulating the activity of ERKs.
The cyclolignan PPP is an inhibitor of phosphorylation of IGF-1R and
activation of downstream molecules, without interfering with the highly
homologous insulin receptor (IR). Further, PPP has well established
anti-tumor effects on several in vivo tumor models. We could demonstrate
that PPP also causes downregulation of IGF-1R. Furthermore, the
PPP-induced downregulation of IGF-1R required the expression of wild type
MDM2 E3 ligase, indicating that MDM2-dependent ubiquitination and
degradation of IGF-1R represents an important mechanism in this respect.
Our data also suggest that this effect of PPP plays a role in induction
of apoptosis.
Finally, we demonstrated that PPP in fact induces IGF-1R ubiquitination,
but also temporarily activates ERK1/2. This effect is IGF-1R-specific
since PPP does not affect ERK phosphorylation in IGF-1R negative cells.
Moreover, in the absence of MDM2, PPP-induced activation of ERK did not
occur. The temporary MDM2-dependent ERK phosphorylation induced by PPP
may contribute to the apoptotic effect of this compound.
List of papers:
I. Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Girnita A, Lefkowitz RJ, Larsson O (2005). "{beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase." J Biol Chem 280(26): 24412-9. Epub 2005 May 3
Pubmed
II. Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Vasilcanu D, Girnita A, Lefkowitz RJ, Larsson O (2007). "Beta-arrestin and Mdm2 mediate IGF-1 receptor-stimulated ERK activation and cell cycle progression." J Biol Chem 282(15): 11329-38. Epub 2007 Feb 15
Pubmed
III. Vasilcanu R, Vasilcanu D, rosengren L, Natalishvili N, Sehat B, Yin S, Girnita A, Axelson M, Girnita L, Larsson O (2007). "Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor. Potential mechanistic involvement of MDM2 and beta-arrestin1." (Submitted)
IV. Vasilcanu R, Vasilcanu D, Sehat B, Yin S, Girnita A, Axelson M, Larsson O, Girnita I (2007). "Insulin-like growth factor 1 receptor (IGF-1R) dependent phosphorylation of ERK1/2 but not Akt (PKB) can be induced without receptor autophosphorylation." (Submitted)
I. Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Girnita A, Lefkowitz RJ, Larsson O (2005). "{beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase." J Biol Chem 280(26): 24412-9. Epub 2005 May 3
Pubmed
II. Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Vasilcanu D, Girnita A, Lefkowitz RJ, Larsson O (2007). "Beta-arrestin and Mdm2 mediate IGF-1 receptor-stimulated ERK activation and cell cycle progression." J Biol Chem 282(15): 11329-38. Epub 2007 Feb 15
Pubmed
III. Vasilcanu R, Vasilcanu D, rosengren L, Natalishvili N, Sehat B, Yin S, Girnita A, Axelson M, Girnita L, Larsson O (2007). "Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor. Potential mechanistic involvement of MDM2 and beta-arrestin1." (Submitted)
IV. Vasilcanu R, Vasilcanu D, Sehat B, Yin S, Girnita A, Axelson M, Larsson O, Girnita I (2007). "Insulin-like growth factor 1 receptor (IGF-1R) dependent phosphorylation of ERK1/2 but not Akt (PKB) can be induced without receptor autophosphorylation." (Submitted)
Issue date: 2007-05-25
Rights:
Publication year: 2007
ISBN: 978-91-7357-244-6
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