Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations - PubMed (original) (raw)

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Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations

Woody Han et al. Cancer Lett. 2012.

Abstract

The epidermal growth factor receptor (EGFR) pathway is one of the most dysregulated molecular pathways in human cancers. Despite its well-established importance in tumor growth, progression and drug-resistant phenotype over the past several decades, targeted therapy designed to circumvent EGFR has yielded only modest clinical success in cancer patients, except those with non-small cell lung cancer (NSCLC) carrying EGFR activation mutations. However, almost all of these NSCLC patients eventually developed resistance to small molecule EGFR kinase inhibitors. These disappointing outcomes are, in part, due to the high complexity and the interactive nature of the EGFR signaling network. More recent compelling evidence further indicates that EGFR functionality can be dependent on its subcellular location. In this regard, EGFR undergoes translocation into different organelles where it elicits distinctly different functions than its best known activity as a plasma membrane-bound receptor tyrosine kinase. EGFR can be shuttled into the cell nucleus and mitochondrion upon ligand binding, radiation, EGFR-targeted therapy and other stimuli. Nuclear EGFR behaves as transcriptional regulator, tyrosine kinase, and mediator of other physiological processes. The role of mitochondrial EGFR remains poorly understood but it appears to regulate apoptosis and autophagy. While studies using patient tumors have shown nuclear EGFR to be an indicator for poor clinical outcomes in cancer patients, the impact of mitochondrial EGFR on tumor behavior and patient prognosis remains to be defined. Most recently, several lines of evidence suggest that mislocated EGFR may regulate tumor response to therapy and that plasma membrane-bound EGFR elicits survival signals independent of its kinase activity. In light of these recent progresses and discoveries, we will outline in this minireview an emerging line of research that uncovers and functionally characterizes several novel modes of EGFR signaling that take center stage in the cell nucleus, mitochondrion and other subcellular compartments. We will also discuss the clinical implications of these findings in the rationale design for therapeutic strategy that overcomes tumor drug resistance.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

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Figures

Figure 1

Figure 1. The plasma membrane-bound EGFR/EGFRvIII signaling is consisted of the kinase-dependent and -independent modes of actions

A: Kinase-dependent functions. Upon ligand binding, EGFR becomes activated and phosphorylated at multiple tyrosine residues including those within its kinase domain. Phosphorylated EGFR then recruits and phosphorylates downstream signaling molecules. The major pathways downstream of EGFR include those mediated by PLC-γ–PKC, Ras-Raf-MEK, PI3-K-Akt-mTOR and JAK2-STAT3. In addition, EGFR can directly interact with and phosphorylate STAT3 transcription factor. EGFRvIII is constitutively active independent of ligand stimulation. B: Kinase-independent functions. Co-expression of the kinase-dead EGFR K721M mutant with HER2 rescued the inability of the mutant EGFR to activate Akt and MAPK. Kinase-dead EGFR D813A mutant may activate Akt via undefined mechanisms. Independent of its kinase activity, EGFR also interacts with and stabilizes plasma membrane-bound SGLT1, leading to glucose uptake and increased intracellular glucose levels. Our laboratory recently reported that EGFR and EGFRvIII associated with and sequestered the proapoptotic protein PUMA in the cytoplasm independent on EGF stimulation or its kinase activity. The EGFR-PUMA and EGFRvIII-PUMA interactions contribute to reduced apoptosis and survival.

Figure 2

Figure 2. The nuclear mode of EGFR/EGFRvIII signaling network

EGFR nuclear transport can be induced by EGF, Akt phosphorylation, radiation and cisplatin, and conversely, inhibited by lapatinib, dasatinib and celecoxib. Nuclear EGFR has three major functions: (i) gene regulation, (ii) kinase function, and (iii) protein-protein interactions. Via these actions, nuclear EGFR is implicated in a number of physiological and pathological processes, such as proliferation, inflammation, metastasis, DNA repair, and resistance to DNA-damaging radiation and alkylating anti-cancer agents. Nuclear EGFRvIII activates COX-2 gene expression.

Figure 3

Figure 3. The mitochondrial mode of EGFR/EGFRvIII signaling pathway

A: EGFR mitochondrial import can be constitutive and the extent can be enhanced by apoptosis inducers (staurosporine and anisomycin), EGF, c-Src, Iressa, cetuximab and rapamycin. Conversely, EGFR mitochondrial transport can be blocked by 3-methyadenine (inhibitor of autophagy and PI-3K) and etoposide. Mitochondrial EGFR retains its tyrosine kinase activity and phosphorylates CoxII; however, the consequence of the phosphorylation is not yet defined. The mitochondrial EGFR-CoxII complex can include c-Src; however, the effects of this interaction are still unknown. Furthermore, mitochondrial accumulation of EGFR led to compromised apoptotic response and resistance to Iressa treatments, while the underlying mechanisms are still undetermined. B: EGFRvIII mitochondrial import is constitutive and can be further enhanced by apoptosis inducers (staurosporine and anisomycin) and by Iressa. Mitochondrial accumulation of EGFRvIII rendered tumor cells highly resistant to apoptotic death and to Iressa treatments, while the mechanisms are still not identified.

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