Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction

Bergeron, John J.M.; Guglielmo, Gianni M. Di; Dahan, Sophie; Dominguez, Michel; Posner, Barry I.

doi:10.1146/annurev-biochem-060815-014659

Cited by 104 publications

(104 citation statements)

References 151 publications

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“…The first step in the regulation of EGFR signaling takes place at the PM, where the EGFR is internalized through multiple endocytic pathways with different morphological, molecular, and kinetic features that influence receptor activity and fate (Barbieri et al ., ; Bergeron et al ., ). Both clathrin‐mediated endocytosis (CME) and several NCE pathways are involved in EGFR internalization (Barbieri et al ., ).…”

Section: Canonical Ligand‐dependent Egfr Signaling Pathwaymentioning

confidence: 97%

Emerging functions of the EGFR in cancer

2017

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The physiological function of the epidermal growth factor receptor (EGFR) is to regulate epithelial tissue development and homeostasis. In pathological settings, mostly in lung and breast cancer and in glioblastoma, the EGFR is a driver of tumorigenesis. Inappropriate activation of the EGFR in cancer mainly results from amplification and point mutations at the genomic locus, but transcriptional upregulation or ligand overproduction due to autocrine/paracrine mechanisms has also been described. Moreover, the EGFR is increasingly recognized as a biomarker of resistance in tumors, as its amplification or secondary mutations have been found to arise under drug pressure. This evidence, in addition to the prominent function that this receptor plays in normal epithelia, has prompted intense investigations into the role of the EGFR both at physiological and at pathological level. Despite the large body of knowledge obtained over the last two decades, previously unrecognized (herein defined as ‘noncanonical’) functions of the EGFR are currently emerging. Here, we will initially review the canonical ligand‐induced EGFR signaling pathway, with particular emphasis to its regulation by endocytosis and subversion in human tumors. We will then focus on the most recent advances in uncovering noncanonical EGFR functions in stress‐induced trafficking, autophagy, and energy metabolism, with a perspective on future therapeutic applications.

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Section: Canonical Ligand‐dependent Egfr Signaling Pathwaymentioning

confidence: 97%

Emerging functions of the EGFR in cancer

2017

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“…The importance of the endosomal system in regulating signalling for a range of peptide hormones and growth factors, including G-protein coupled receptors, such as glucagon, has now been firmly established (24). …”

Section: Endosomal Signalling and Its Regulationmentioning

confidence: 99%

Insulin Signalling: The Inside Story

Posner

2017

Canadian Journal of Diabetes

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Insulin signalling begins with binding to its cell surface insulin receptor (IR), which is a tyrosine kinase. The insulin receptor kinase (IRK) is subsequently autophosphorylated and activated to tyrosine phosphorylate key cellular substrates that are essential for entraining the insulin response. Although IRK activation begins at the cell surface, it is maintained and augmented following internalization into the endosomal system (ENS). The peroxovanadium compounds (pVs) were discovered to activate the IRK in the absence of insulin and lead to a full insulin response. Thus, IRK activation is both necessary and sufficient for insulin signalling. Furthermore, this could be shown to occur with activation of only the endosomal IRK. The mechanism of pV action was shown to be the inhibition of IRK-associated phosphotyrosine phosphatases (PTPs). Our studies showed that the duration and intensity of insulin signalling are modulated within ENS by the recruitment of cellular substrates to ENS; intra-endosomal acidification, which promotes dissociation of insulin from the IRK; an endosomal acidic insulinase, which degrades intra-endosomal insulin; and IRK-associated PTPs, which dephosphorylate and, hence, deactivate the IRK. Therefore, the internalization of IRKs is central to insulin signalling and its regulation.

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“…The receptor tyrosine kinase (RTKs)-like orphan receptors (RORs), like all other RTKs 13 , possesses extracellular ligand-binding domain, yet their ligands, cellular effects, and downstream signaling pathways are largely unknown 14 . The two ROR family members, ROR1 and ROR2, were originally found to be involved in skeletal, cardiorespiratory, and neurological development 15,16 .…”

Section: Introductionmentioning

confidence: 99%

A ROR1–HER3–lncRNA signalling axis modulates the Hippo–YAP pathway to regulate bone metastasis

et al. 2017

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Bone metastases remain as a serious health concern because of limited therapeutic options. Here, we report that crosstalk between ROR1-HER3 and the Hippo-YAP pathway promotes breast cancer bone metastasis in a long noncoding RNA-dependent fashion. Mechanistically, the orphan receptor tyrosine kinase ROR1 phosphorylates HER3 at a previously unidentified site Tyr1307, upon neuregulin stimulation, independently of other ErbB family members. p-HER3 Tyr1307 recruits the LLGL2-MAYA-NSUN6 RNA-protein complex to methylate Hippo/MST1 at Lys59. This methylation leads to MST1 inactivation and activation of YAP target genes in tumor cells, which elicits osteoclast differentiation and bone metastasis. Furthermore, increased ROR1, p-HER3 Tyr1307 and MAYA levels correlate with tumor metastasis and unfavorable outcomes. Our data provide insights into the mechanistic regulation and linkage of the ROR1-HER3 and Hippo-YAP pathway in cancer-specific context, and also imply valuable therapeutic targets for bone metastasis and possible therapy-resistant tumors.

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Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction

Cited by 104 publications

References 151 publications

Emerging functions of the EGFR in cancer

Emerging functions of the EGFR in cancer

Insulin Signalling: The Inside Story

A ROR1–HER3–lncRNA signalling axis modulates the Hippo–YAP pathway to regulate bone metastasis

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