A soluble ectodomain of LRIG1 inhibits cancer cell growth by attenuating basal and ligand-dependent EGFR activity

Goldoni, Silvia; Iozzo, Rex A.; Kay, Paul; Campbell, Shelly; McQuillan, Angela; Agnew, Christopher; Zhu, Jian Xhu; Keene, D.; Reed, Charles C.; Iozzo, Renato V.

doi:10.1038/sj.onc.1209803

Cited by 64 publications

(73 citation statements)

References 64 publications

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“…2A) (Yi et al, 2010). Consistent with the above study, a recombinant fragment of LRIG1 corresponding to the LRR domain was shown to attenuate EGFR signalling and EGFR-driven cell proliferation by acting as a high-affinity competitive inhibitor of EGF binding to the EGFR (Goldoni et al, 2007). It remains to be determined whether, and under which conditions, bioactive LRIG1 extracellular domain (LED) fragments are generated by processing of the endogenous LRIG1 protein.…”

Section: Lrig1mentioning

confidence: 59%

Regulation of epidermal growth factor receptor signalling by inducible feedback inhibitors

Segatto¹,

Anastasi²,

Alemà

2011

Journal of Cell Science

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Signalling by the epidermal growth factor receptor (EGFR) controls morphogenesis and/or homeostasis of several tissues from worms to mammals. The correct execution of these programmes requires the generation of EGFR signals of appropriate strength and duration. This is obtained through a complex circuitry of positive and negative feedback regulation. Feedback inhibitory mechanisms restrain EGFR activity in time and space, which is key to ensuring that receptor outputs are commensurate to the cell and tissue needs. Here, we focus on the emerging field of inducible negative feedback regulation of the EGFR in mammals. In mammalian cells, four EGFR inducible feedback inhibitors (IFIs), namely LRIG1, RALT (also known as MIG6 and ERRFI1), SOCS4 and SOCS5, have been discovered recently. EGFR IFIs are expressed de novo in the context of early or delayed transcriptional responses triggered by EGFR activation. They all bind to the EGFR and suppress receptor signalling through several mechanisms, including catalytic inhibition and receptor downregulation. Here, we review the mechanistic basis of IFI signalling and rationalise the function of IFIs in light of gene-knockout studies that assign LRIG1 and RALT an essential role in restricting cell proliferation. Finally, we discuss how IFIs might participate in system control of EGFR signalling and highlight the emerging roles for IFIs in the suppression of EGFR-driven tumorigenesis.

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Section: Lrig1mentioning

confidence: 59%

Regulation of epidermal growth factor receptor signalling by inducible feedback inhibitors

Segatto¹,

Anastasi²,

Alemà

2011

Journal of Cell Science

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“…Previous evidence suggests that decorin, as a key component of the tumor stroma, interacts with various growth factors such as EGF and TGF-β and is necessary for cell migration (34,35). Furthermore, it may regulate the action of several tyrosine-kinase receptors, including the EGFR, ERK and insulin-like growth factor receptor I (36,37). Thereupon, whether similar mechanisms of ASPN play a role in tumors warrants attention.…”

Section: Discussionmentioning

confidence: 99%

Asporin participates in gastric cancer cell growth and migration by influencing EGF receptor signaling

2015

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Abstract. Asporin (ASPN), a novel member of the small leucine-rich proteoglycan (SLRP) family, serves as a key component of the tumor stroma and has been reported to be abnormally expressed in certain types of tumors. Specifically, the proteoglycan was proven to activate the coordinated invasion of scirrhous gastric cancer and cancer-associated fibroblasts. However, the role of ASPN in cancer cell growth and metastasis has not yet been addressed. In the present study, we aimed to evaluate the tumoricidal benefits of ASPN on tumorigenesis and progression of gastric cancer. Firstly, it was demonstrated that ASPN was overexpressed in gastric carcinoma tissues when compared to the corresponding non-cancerous tissues, and it had varied levels of expression in gastric cancer epithelial cell lines. Additionally, we assessed the effects of transient siRNA-mediated ASPN knockdown on gastric cancer cells. ASPN silencing inhibited proliferation and suppressed the migration of immortalized neoplastic epithelial cells. Furthermore, at the molecular level, we found that downregulation of ASPN blocked the anti-apoptotic molecule Bcl-2, increased the expression of pro-apoptotic molecule Bad, reduced the expression of migration-related proteins CD44 and matrix metalloproteinase (MMP)-2, and abrogated the activation of the phosphorylation status of ERK and epidermal growth factor (EGF) and its receptor (EGFR). Collectively, our findings indicate that ASPN is upregulated and plays an oncogenic role in gastric cancer progression and metastasis by influencing the EGFR signaling pathway.

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“…Although the precise mechanism by which Lrig1 destabilizes Met receptor is still unknown, it has been proposed that Lrig1 likely acts to facilitate the association of Met with the protein degradation machinery. Based on the premise that the LRR domain is the critical interacting domain between Lrig1 and EGF/ErbB receptors, Goldoni et al (2007) have recently demonstrated that a soluble ectodomain of Lrig1 containing only the LRR domain is sufficient to antagonize both ligand-independent and liganddependent EGFR activation in a non-cell-autonomous manner. In contrast to the full-length Lrig1 protein, the inhibition occurs without noticeable effects on internalization and degradation of the receptors, revealing that in mammals Lrig1 could also restricts EGFR activation by a Cbl-independent mechanism.…”

Section: Discussionmentioning

confidence: 99%

Lrig1 Is an Endogenous Inhibitor of Ret Receptor Tyrosine Kinase Activation, Downstream Signaling, and Biological Responses to GDNF

Ledda¹,

Bieraugel²,

Fard³

et al. 2008

J. Neurosci.

113

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Glial cell line-derived neurotrophic factor (GDNF)/Ret signaling has potent trophic effects on ventral midbrain dopaminergic, motor, sensory, and sympathetic neurons. The molecular mechanisms that restrict Ret receptor tyrosine kinase activation are not well understood. Here, we show that Lrig1, a transmembrane protein containing leucine-rich repeats and Ig-like domains in its extracellular region, acts in a negative feedback loop to regulate the activity of Ret receptor tyrosine kinase. In particular, we demonstrate that Lrig1 is capable of physically interacting with Ret and that Lrig1/Ret association inhibits GDNF binding, recruitment of Ret to lipid rafts, receptor autophosphorylation, and mitogen-activated protein kinase (MAPK) activation in response to GDNF. In neuronal cells, Lrig1 overexpression also inhibits GDNF/Ret-induced neurite outgrowth in a cell-autonomous manner. Downregulation of Lrig1 using small interference RNA knock-down experiments potentiates both neuronal differentiation and MAPK activation in response to GDNF. Together, these results provide an insight into Lrig1 function and establish a new physiological mechanism to restrict signaling and biological responses induced by GDNF and Ret in neuronal cells.

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A soluble ectodomain of LRIG1 inhibits cancer cell growth by attenuating basal and ligand-dependent EGFR activity

Cited by 64 publications

References 64 publications

Regulation of epidermal growth factor receptor signalling by inducible feedback inhibitors

Regulation of epidermal growth factor receptor signalling by inducible feedback inhibitors

Asporin participates in gastric cancer cell growth and migration by influencing EGF receptor signaling

Lrig1 Is an Endogenous Inhibitor of Ret Receptor Tyrosine Kinase Activation, Downstream Signaling, and Biological Responses to GDNF

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