Mechanisms of Receptor Tyrosine-Protein Kinase ErbB-3 (ERBB3) Action in Human Neoplasia

Black, Laurel; Longo, Jody Fromm; Carroll, Steven L.

doi:10.1016/j.ajpath.2019.06.008

Cited by 44 publications

(35 citation statements)

References 99 publications

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“…However, even in this case, overlapping of the single-cell response distributions for EGF and HRG was large especially for B1/B2 and B1/B4 combinations. The distributions were most clearly separated for the B1/B3 combination, supporting the findings of recent studies suggesting that ERBB3 is a key factor in fate determination [24]. Nevertheless, the bet-hedging properties of the cell populations under conditions of a clear cell fate change indicate that exploration of the wide state-space is required for the fate changes.…”

Section: Information Analysis Is a Generalization Of The Linear Corresupporting

confidence: 84%

Cell-to-cell diversification in ERBB-RAS-MAPK signal transduction that produces cell-type specific growth factor responses

Miyagi

Hiroshima

Sako

2019

Preprint

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Growth factors regulate cell fates, including their proliferation, differentiation, survival, and death, according to the cell type. Even when the response to a specific growth factor is deterministic for collective cell behavior, significant levels of fluctuation are often observed between single cells. Statistical analyses of single-cell responses provide insights into the mechanism of cell fate decisions but very little is known about the distributions of the internal states of cells responding to growth factors. Using multi-color immunofluorescent staining, we have here detected the phosphorylation of seven elements in the early response of the ERBB-RAS-MAPK system to two growth factors. Among these seven elements, five were analyzed simultaneously in distinct combinations in the same single cells. Although principle component analysis suggested cell-type and input specific phosphorylation patterns, cell-to-cell fluctuation was large. Mutual information analysis suggested that cells use multitrack (bush-like) signal transduction pathways under conditions in which clear cell fate changes have been reported. The clustering of single-cell response patterns indicated that the fate change in a cell population correlates with the large entropy of the response, suggesting a bet-hedging strategy is used in decision making. A comparison of true and randomized datasets further indicated that this large variation is not produced by simple reaction noise, but is defined by the properties of the signal-processing network. Author SummaryHow extracellular signals, such as growth factors (GFs), induce fate changes in biological cells is still not fully understood. Some GFs induce cell proliferation and others induce differentiation by stimulating a common reaction network. Although the response to each GF is reproducible for a cell population, not all single cells respond similarly. The question that arises is whether a certain GF conducts all the responding cells in the same direction during a fate change, or if it initially stimulates a variety of behaviors among single cells, from which the cells that move in the appropriate direction are later selected.Our current statistical analysis of single-cell responses suggests that the latter process, which is called a bet-hedging mechanism is plausible. The complex pathways of signal transmission seem to be responsible for this bet-hedging.

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Section: Information Analysis Is a Generalization Of The Linear Corresupporting

confidence: 84%

Cell-to-cell diversification in ERBB-RAS-MAPK signal transduction that produces cell-type specific growth factor responses

Miyagi

Hiroshima

Sako

2019

Preprint

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“…These ligands are structurally related proteins among which there are high-affinity ligands such as epidermal growth factor (EGF), transforming growth factor-α (TGF-α), heparin-binding EGF (HB-EGF) and b-cellulin (BTC), and low-affinity ligands such as amphiregulin (AR), epiregulin (EREG) and epigen (EPGN) [5]. Other ligands belonging to this family are represented by neuregulins (neuregulin 1-4) which bind only to ErbB3 and ErbB4 while ErbB2 is still an orphan receptor [6] (Figure 1). They all derive from integral membrane protein precursors that, after cleavage, give rise to their soluble forms containing a conserved three-loop compact structure, known as the EGF-like domain [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Role of EGFR in the Nervous System

Romanò

Bucci

2020

Cells

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Epidermal growth factor receptor (EGFR) is the first discovered member of the receptor tyrosine kinase superfamily and plays a fundamental role during embryogenesis and in adult tissues, being involved in growth, differentiation, maintenance and repair of various tissues and organs. The role of EGFR in the regulation of tissue development and homeostasis has been thoroughly investigated and it has also been demonstrated that EGFR is a driver of tumorigenesis. In the nervous system, other growth factors, and thus other receptors, are important for growth, differentiation and repair of the tissue, namely neurotrophins and neurotrophins receptors. For this reason, for a long time, the role of EGFR in the nervous system has been underestimated and poorly investigated. However, EGFR is expressed both in the central and peripheral nervous systems and it has been demonstrated to have specific important neurotrophic functions, in particular in the central nervous system. This review discusses the role of EGFR in regulating differentiation and functions of neurons and neuroglia. Furthermore, its involvement in regeneration after injury and in the onset of neurodegenerative diseases is examined.

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“…Epidermal growth factor receptor 3 (ERBB3) is a surface tyrosine kinase receptor belonging to the EGFR/ERBB family [ 12 ]. ERBB receptors are widely expressed in different cell types and play a pivotal role in many cellular functions, including cell growth, division, migration, adhesion, and apoptosis [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

The Clinical Role of Serum Epidermal Growth Factor Receptor 3 in Hepatitis C Virus-Infected Patients with Early Hepatocellular Carcinoma

Caviglia

Abate

Rolle³

et al. 2021

Biology

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Epidermal growth factor receptor 3 (ERBB3) is a surface tyrosine kinase receptor belonging to the EGFR/ERBB family, involved in tumor development and progression. We evaluated the diagnostic and prognostic value of serum ERBB3 measurement in hepatitis C virus (HCV)-infected patients with early hepatocellular carcinoma (HCC). A total of 164 HCV-infected patients (82 with cirrhosis and 82 with early HCC) were included in the study. HCC was classified according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Among patients with HCC, 23 (28%) had a diagnosis of very early tumor (BCLC = 0), while 59 (62%) had a diagnosis of early HCC (BCLC = A). Median overall survival (OS) in patients with HCC was 79.2 (95% CI 51.6–124.8) months. While ERBB3 serum values were similar between patients with cirrhosis and those with HCC (p = 0.993), in the latter, serum ERBB3 ≥ 2860 RU resulted significantly and independently associated with OS (Hazard Ratio = 2.24, 95% CI 1.16–4.35, p = 0.017). Consistently, the 1-, 3-, and 5-year OS rates in patients with serum ERBB3 ≥ 2860 RU were 90% (36/40), 53% (19/36), and 28% (8/29) in comparison to patients with serum ERBB3 < 2860 RU, which were 98% (40/41), 80% (32/40), and 74% (26/35) (Log-rank test; p = 0.014). In conclusion, serum ERBB3 values resulted an independent prognostic factor of patients with early HCC and might be useful to tailor more personalized treatment strategies.

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Mechanisms of Receptor Tyrosine-Protein Kinase ErbB-3 (ERBB3) Action in Human Neoplasia

Cited by 44 publications

References 99 publications

Cell-to-cell diversification in ERBB-RAS-MAPK signal transduction that produces cell-type specific growth factor responses

Cell-to-cell diversification in ERBB-RAS-MAPK signal transduction that produces cell-type specific growth factor responses

Role of EGFR in the Nervous System

The Clinical Role of Serum Epidermal Growth Factor Receptor 3 in Hepatitis C Virus-Infected Patients with Early Hepatocellular Carcinoma

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