A PDZ Domain Protein Interacts with the C-terminal Tail of the Insulin-like Growth Factor-1 Receptor but Not with the Insulin Receptor

Ligensa, Tanja; Krauss, Sonia; Demuth, Dirk; Schumacher, R.; Camonis, Jacques; Jaques, Gabriele; Weidner, K. Michael

doi:10.1074/jbc.m104509200

Cited by 57 publications

(48 citation statements)

References 57 publications

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“…The BCA3 N-terminus, which contains the nuclear-localizing sequence (amino acids 15-21) that accounts for its nuclear localization (Sastri et al, 2005), is responsible for the retention of p65 in the nucleus. In addition to the consensus phosphorylation sites, the carboxyl terminus of BCA3, -F-P-V, corresponds to the consensus binding sequence, -F/Yx-(A/F/V), derived from Type II PDZ domain-containing proteins (Songyang et al, 1997;Ligensa et al, 2001). PDZ domain proteins are typically localized at the cytoplasmic face of the cell membrane where they bind to the carboxyl termini of their substrates, and in many cases contain additional kinase domains (Ponting et al, 1997;Carraway and Sweeney, 2001;Ligensa et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Cloning and functional identification of a novel BCA3 splice

Zhang¹,

Hu²,

Qiao³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. The human breast cancer-associated gene (BCA3) was first discovered in breast and prostate cancer cells lines. In vivo studies have shown that BCA3 is mainly expressed in breast tumor cells and not in normal breast and prostate tissues. To date, 3 splice variants of BCA3 have been reported: a double-absent variant lacking exon 3 and exon 5 (BCA3-1), an exon 3-absent variant (BCA3-2), and full-length BCA3. In this study, we investigated whether a novel BCA3 splice variant exists that lacks only the exon 5-encoding sequence. BCA3 variant splices were subcloned and sequenced using reverse transcription-polymerase chain reaction. The preliminary biological functions of the splices were identified using confocal microscopy and a luciferase assay. The absence of exon 3 and exon 5 influenced the subcellular localization of BCA3 and nuclear factor kappa B (NF-kB)-dependent gene expression. Exon 3 and exon 5 of BCA3 may function together to provide a nuclear localization signal or transport sequence to enter the nucleus, and exon 3 may contain specific sequence(s) or domain(s) that influence the NF-κB signal cascade. The discovery of 10649 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 13 (4): 10648-10656 (2014) Novel BCA3 splice novel BCA3 splicing indicates a new cancer research area, which may increase the understanding of cancer generation and development.

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Section: Discussionmentioning

confidence: 99%

Cloning and functional identification of a novel BCA3 splice

Zhang¹,

Hu²,

Qiao³

et al. 2014

Genet. Mol. Res.

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“…described (16). Activated IGF1R was detected by immunoprecipitation for phosphotyrosine (P-Tyr-100, Cell Signaling Technology) and immunoblotting for IGF1R ␤-subunit.…”

Section: Methodsmentioning

confidence: 99%

The Efficacy of Small Interfering RNAs Targeted to the Type 1 Insulin-like Growth Factor Receptor (IGF1R) Is Influenced by Secondary Structure in the IGF1R Transcript

Bohula

Salisbury

Sohail

et al. 2003

Journal of Biological Chemistry

222

159

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The type 1 insulin-like growth factor receptor (IGF1R) is often overexpressed by tumors and mediates growth and apoptosis protection. We previously showed that antisense reagents complementary to the IGF1R translation start site enhance radio-and chemosensitivity and impair Atm function. However these agents induce relatively modest IGF1R down-regulation and affect insulin receptor levels. To identify alternative sites for molecular targeting, we utilized scanning oligonucleotide arrays to probe the secondary structure of IGF1R mRNA. This strategy enabled selection of antisense oligonucleotides that generated high heteroduplex yield with IGF1R but not insulin receptor transcripts. Antisense oligonucleotides that hybridized strongly to IGF1R mRNA caused IGF1R down-regulation within intact tumor cells, whereas weakly hybridizing oligonucleotides were inactive. Furthermore, the ability of small interfering RNAs (siRNAs) to block IGF1R expression correlated with the accessibility of the target sequence within the transcript. Thus, siRNAs corresponding to weakly hybridizing oligonucleotides caused minor IGF1R down-regulation, whereas siRNAs homologous to accessible targets induced profound sequencespecific IGF1R gene silencing, blocked IGF signaling, and enhanced tumor cell radiosensitivity. This indicates that secondary structure in the target transcript has a major effect on siRNA efficacy. These findings have implications for siRNA design and suggest that IGF1R-targeting agents incorporating this mode of action have potential as anticancer therapy.The type 1 insulin-like growth factor receptor (IGF1R) 1 is often overexpressed by tumors (1-3), and IGF1R activation mediates tumor cell proliferation, motility, and protection from apoptosis (4). Tumor growth can be inhibited in vivo by blocking IGF1R expression using antisense agents targeting the IGF1R translation start site (TSS) (5). We previously showed that TSS antisense oligonucleotides (ASOs) and antisense RNA enhanced tumor cell sensitivity to cytotoxic drugs and ionizing radiation and impaired the function of Atm (6, 7). However we could not suppress IGF1R expression by more than 80% and sought to identify alternative sites for molecular targeting.Intramolecular folding of mRNAs renders all but 5-10% of most transcripts inaccessible to binding of complementary nucleic acids, but the complex secondary structure of long mRNAs is not amenable to accurate modeling (8 -11). We used an array-based screen (12) to identify sites within the human IGF1R transcript that were accessible to RNase-H-mediated cleavage. This information on secondary structure allowed us to identify molecular agents that induced IGF1R down-regulation without affecting insulin receptor (IR) expression. Structural constraints were shown to govern the activity of ASOs and also of small interfering RNAs (siRNAs) that mediate RNA interference (RNAi) in mammalian cells (13). MATERIALS AND METHODSOligonucleotides-A 12-mer deoxyribophosphodiester oligonucleotide library (dN 12 ) was synthesized as de...

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“…proteins that interact with the IGF-1R also interact with the IR, but there is at least one IGF-1R-interacting protein that was identified in a yeast two-hybrid system that does not interact with the IR (36). We were therefore interested to determine whether RACK1 could interact with the IR as well as with the IGF-1R.…”

Section: Rack1 Interacts the Insulin Receptor With Kinase-inactive Igmentioning

confidence: 99%

RACK1 Is an Insulin-like Growth Factor 1 (IGF-1) Receptor-interacting Protein That Can Regulate IGF-1-mediated Akt Activation and Protection from Cell Death

Kiely¹,

Sant²,

O’Connor³

2002

Journal of Biological Chemistry

136

133

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The insulin receptor and insulin-like growth factor 1 receptor (IGF-1R), activated by their ligands, control metabolism, cell survival, and proliferation. Although the signaling pathways activated by these receptors are well characterized, regulation of their activity is poorly understood. To identify regulatory proteins we undertook a two-hybrid screen using the IGF-1R ␤-chain as bait. This screen identified Receptor for Activated C Kinases (RACK1) as an IGF-1R-interacting protein. RACK1 also interacted with the IGF-1R in fibroblasts and MCF-7 cells and with endogenous insulin receptor in COS cells. Interaction with the IGF-1R did not require tyrosine kinase activity or receptor autophosphorylation but did require serine 1248 in the C terminus. Overexpression of RACK1 in either R؉ fibroblasts or MCF-7 cells inhibited IGF-1-induced phosphorylation of Akt, whereas it enhanced phosphorylation of Erks and Jnks. Src, the p85 subunit of phosphatidylinositol 3-kinase, and SHP-2 were all associated with RACK1 in these cells. Interestingly, the proliferation of MCF-7 cells was enhanced by overexpression of RACK1, whereas IGF-1-mediated protection from etoposide killing was greatly reduced. Altogether the data indicate that RACK1 is an IGF-1R-interacting protein that can modulate receptor signaling and suggest that RACK1 has a particular role in regulating Akt activation and cell survival.The insulin and IGF-1 1 receptors (IR and IGF-1R) belong to a family of tyrosine kinase receptors that also includes the insulin-related receptor. They are tetrameric receptors made up of two ␣-subunits that bind the ligands insulin, IGF-1 or IGF-2, and two ␤-subunits that share high homology in their kinase domains (reviewed in Ref. 1). These receptors are homologous to a receptor found in the nematode Caenorhabditis elegans and in Drosophila, and they activate an evolutionarily conserved metabolic and survival signaling pathway that includes insulin-related substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3-K), the serine/threonine kinase Akt, and the Forkhead family of transcription factors (2-5).

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A PDZ Domain Protein Interacts with the C-terminal Tail of the Insulin-like Growth Factor-1 Receptor but Not with the Insulin Receptor

Cited by 57 publications

References 57 publications

Cloning and functional identification of a novel BCA3 splice

Cloning and functional identification of a novel BCA3 splice

The Efficacy of Small Interfering RNAs Targeted to the Type 1 Insulin-like Growth Factor Receptor (IGF1R) Is Influenced by Secondary Structure in the IGF1R Transcript

RACK1 Is an Insulin-like Growth Factor 1 (IGF-1) Receptor-interacting Protein That Can Regulate IGF-1-mediated Akt Activation and Protection from Cell Death

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