The Transmembrane Heregulin Precursor Is Functionally Active

Aguilar, Zuleima; Slamon, Dennis J.

doi:10.1074/jbc.m103442200

Cited by 26 publications

(23 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Menendez et al (2006) found Herceptin to inhibit certain breast cancer cells that do not overexpress ErbB2 but do overexpress heregulin. Although MDA-MB-231 does not overexpress ErbB2 or Grb7, it does overexpress heregulin and promotes tumourigenicity and metastasis of breast cancer cells (Aguilar and Slamon, 2001). Interestingly, the Grb7 peptide inhibits MDA-MB-231 cells and not MCF-7, which does not overexpress heregulin, suggests there may be a correlation between Grb7 peptide-induced response and heregulin overexpression.…”

Section: Discussionmentioning

confidence: 99%

Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

et al. 2007

View full text Add to dashboard Cite

Grb7 has potential importance in the progression of cancer. We have previously identified a novel peptide that binds to the SH2 domain of Grb7 and inhibits its association with several different receptor tyrosine kinases. We have synthesised the Grb7 peptide, G7-18NATE, with two different cell penetrating peptides, Penetratin and Tat. In this study, we have shown that both Penetratin-and Tat-conjugated G7-18NATE peptides are able to inhibit the proliferation of SK-BR-3, ZR-75-30, MDA-MB-361 and MDA-MB-231 breast cancer cells. There was no significant effects on breast cancer MCF-7cells, non-malignant MCF 10A or 3T3 cells. In addition, there was no significant inhibition of proliferation by Penetratin or Tat alone or by their conjugates with arbitrary peptide sequence in any of the cell lines tested. We determined the EC 50 of G7-18NATE-P peptide for SK-BR-3 cell proliferation to be 7.663 Â 10 À6 M. Co-treatment of G7-18NATE-P peptide plus Doxorubicin in SK-BR-3 breast cancer cells resulted in an additional inhibition of proliferation, resulting in 56 and 84% decreases in the Doxorubicin EC 50 value in the presence of 5 Â 10 À6 and 1.0 Â 10 À5 M G7-18NATE-P peptide, respectively. Importantly, the co-treatment with Doxorubicin and the delivery peptide did not change the Doxorubicin EC 50 . Since Grb7 associates with ErbB2, we assessed whether the peptide inhibitor would have a combined effect with a molecule that targets ErbB2, Herceptin. Co-treatment of Herceptin plus 1.0 Â 10 À5 M G7-18NATE-P peptide in SK-BR-3 cells resulted in a 46% decrease in the Herceptin EC 50 value and no decrease following the co-treatment with Herceptin and penetratin alone. This Grb7 peptide has potential to be developed as a therapeutic agent alone, in combination with traditional chemotherapy, or in combination with other targeting molecules.

show abstract

Section: Discussionmentioning

confidence: 99%

Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

et al. 2007

View full text Add to dashboard Cite

show abstract

“…3, A and B, representative blots), consistent with the expression of multiple NRG splice variants. The molecular size of several of these isoforms corresponds to known masses of recombinant NRG proteins (1,24,35,43), including the 115-kDa species that is immunoreactive to both the intracellular and extracellular domain antibodies. The 183-kDa band (Fig.…”

Section: Expression and Localization Of Erbb2 Erbb3mentioning

confidence: 99%

Regulation of neuregulin/ErbB signaling by contractile activity in skeletal muscle

LeBrasseur

Coté

Miller

et al. 2003

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

(NRG) and the ErbB receptors in skeletal muscle biology include myogenesis, ACh receptor expression, and glucose transport. To date, however, the physiological regulation of NRG/ErbB signaling has not been examined. We tested the hypothesis that contractile activity in vivo induces NRG/ ErbB activation. Rat hindlimb muscle contraction was elicited with a single bout of electrical stimulation (RX) or treadmill running (EX). Western blot and immunofluorescence confirmed the expression of multiple NRG isoforms and the ErbB2, ErbB3, and ErbB4 receptors in adult skeletal muscle. Both RX and EX significantly increased phosphorylation of all NRG receptors. Furthermore, contraction induced a shift in the expression profile of NRG, consistent with proteolytic processing of a transmembrane isoform. Thus two distinct modes of exercise activated processing of NRG with concomitant stimulation of ErbB2, ErbB3, and ErbB4 signaling in vivo. To our knowledge, this is the first demonstration of physiological regulation of NRG/ErbB signaling in any organ and implicates this pathway in the metabolic and proliferative responses of skeletal muscle to exercise. exercise; growth factor; receptor tyrosine kinase THE PROLIFERATIVE AND METABOLIC responses of skeletal muscle to contractile activity involve the complex integration of both intra-and intercellular signaling pathways. The activation of diverse intracellular kinase cascades has been demonstrated in skeletal muscle, and these have been associated with fiber hypertrophy and alterations in metabolism. The extracellular stimuli and cell-cell interactions that trigger the activation of these pathways during and after exercise, however, have not been elucidated. In multiple cell types, growth factors relay key extracellular signals to trigger diverse cellular events via receptor tyrosine kinases (RTKs) (9). One such candidate system in the regulation of exercise signaling that has pleiotrophic effects in skeletal muscle is neuregulin (NRG) and its cognate RTKs ErbB2, ErbB3, and ErbB4.The NRGs (also known as heregulin, neu differentiation factor, ACh receptor-inducing activity, glial growth factor II, and sensory motor neuron-derived factor) are a complex family of proteins structurally related to the classical polypeptide mitogen-epidermal growth factor (EGF; see Ref. 19). More than 15 distinct soluble and membrane-anchored NRG isoforms result from alternative splicing of mRNA from one of four known NRG genes (21). All NRGs identified to date feature an EGF-like motif that is both necessary and sufficient for biological activity (6, 29). NRG signals are mediated via activation of the type I subfamily RTKs: ErbB2 (HER2/Neu), ErbB3 (HER3), and ErbB4 (HER4) (7,13, 30,41). Heteromeric complexes of ErbB2, ErbB3, and ErbB4 and homomeric ErbB4 are activated by NRG binding and lead to phosphorylation of cytoplasmic tyrosine residues that initiate a diverse array of downstream signaling events (5, 46).NRGs activate growth, differentiation, and survival signaling pathways in multiple cell ty...

show abstract

“…The result is a soluble NRG1 ligand containing both the N-terminal segments and the EGFlike domain, equivalent to NRG1 ligands obtained by direct secretion. However, direct activation of cells through cell-cell contacts between receptor-expressing cells and cells expressing membrane-bound NRG1 has also been demonstrated (26). For comparison, EGF is also synthesized as a 190-kDa transmembrane precursor protein that, in contrast to NRG1, undergoes cleavage both N-terminal and C-terminal to the EGF domain, producing a small peptide ligand (ϳ6 kDa) for EGFR (27)(28)(29) (Fig.…”

mentioning

confidence: 99%

The N-terminal Domains of Neuregulin 1 Confer Signal Attenuation

Warren

Kani

Landgraf

2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Degradation of activated ERBB receptors is an important mechanism for signal attenuation. However, compared with epidermal growth factor (EGF) receptor, the ERBB2/ERBB3 signaling pair is considered to be attenuation-deficient. The ERBB2/ERBB3 ligands of the neuregulin family rely on an EGFlike domain for signaling and are generated from larger membrane-bound precursors. In contrast to EGF, which is processed to yield a 6-kDa peptide ligand, mature neuregulins retain a variety of segments N-terminal to the EGF-like domain. Here we evaluate the role of the N-terminal domain of neuregulin 1 in signaling and turnover of ERBB2/ERBB3. Our data suggest that whereas the EGF-like domain of neuregulin 1 is required and sufficient for the formation of active receptor heterodimers, the presence of the N-terminal Ig-like domain is required for efficient signal attenuation. This manifests itself for both ERBB2 and ERBB3 but is more pronounced and coupled directly to degradation for ERBB3. When stimulated with only the EGF-like domain, ERBB3 shows degradation rates comparable with constitutive turnover, but stimulation with full-length neuregulin 1 resulted in receptor degradation at rates that are comparable with activated EGF receptor. Most of the enhancement in downregulation was maintained after replacing the Ig-like domain with a thioredoxin protein of comparable size but different amino acid composition, suggesting that the physical presence but not specific properties of the Ig-like domain are needed. This sequence-independent effect of the N-terminal domain correlates with an enhanced ability of full-size neuregulin 1 to disrupt higher order oligomers of the ERBB3 extracellular domains in vitro.

show abstract

The Transmembrane Heregulin Precursor Is Functionally Active

Cited by 26 publications

References 48 publications

Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

Regulation of neuregulin/ErbB signaling by contractile activity in skeletal muscle

The N-terminal Domains of Neuregulin 1 Confer Signal Attenuation

Contact Info

Product

Resources

About