Irreversible modifications of receptor tyrosine kinases

Kreitman, Matthew; Noronha, Ashish; Yarden, Yosef

doi:10.1002/1873-3468.13095

Cited by 21 publications

(13 citation statements)

References 143 publications

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“…Reciprocally, using antibodies specific to the carboxyl-terminal tag confirmed parallel depletion of full-length HER3. Notably, several RTKs serve as substrates of two members of the disintegrin and metalloproteinase domain-containing family, ADAM10 and ADAM17 [35]. Hence, we employed a line of fibroblasts that expresses no ADAM10.…”

Section: An Anti-her3 Antibody Prevents Osimertinib-induced Upregulatmentioning

confidence: 99%

Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor

Romaniello

Marrocco

Nataraj

et al. 2020

Cancers

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Although two growth factor receptors, EGFR and HER2, are amongst the best targets for cancer treatment, no agents targeting HER3, their kinase-defective family member, have so far been approved. Because emergence of resistance of lung tumors to EGFR kinase inhibitors (EGFRi) associates with compensatory up-regulation of HER3 and several secreted forms, we anticipated that blocking HER3 would prevent resistance. As demonstrated herein, a neutralizing anti-HER3 antibody we generated can clear HER3 from the cell surface, as well as reduce HER3 cleavage by ADAM10, a surface metalloproteinase. When combined with a kinase inhibitor and an anti-EGFR antibody, the antibody completely blocked patient-derived xenograft models that acquired resistance to EGFRi. We found that the underlying mechanism involves posttranslational downregulation of HER3, suppression of MET and AXL upregulation, as well as concomitant inhibition of AKT signaling and upregulation of BIM, which mediates apoptosis. Thus, although HER3 is nearly devoid of kinase activity, it can still serve as an effective drug target in the context of acquired resistance. Because this study simulated in animals the situation of patients who develop resistance to EGFRi and remain with no obvious treatment options, the observations presented herein may warrant clinical testing.

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Section: An Anti-her3 Antibody Prevents Osimertinib-induced Upregulatmentioning

confidence: 99%

Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor

Romaniello

Marrocco

Nataraj

et al. 2020

Cancers

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“…The glycoproteins are then subjected to partial de-glycosylation, and transferred to the Golgi compartment for more complex glycosylation [13,38]. As already described in several reviews, irreversible RTK modifications, such as proteolytic cleavage events, are related to changes in intracellular localization [36,39,40].…”

Section: Subcellular Localization Of Receptor Tyrosine Kinases May Gementioning

confidence: 99%

Mutations of FLT3 receptor affect its surface glycosylation, intracellular localization, and downstream signaling

Takahashi

2020

Leukemia Research Reports

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This review describes the effects of FLT3 mutations that alter its intracellular localization and modify its glycosylation, leading to differences in downstream signaling pathways. The most common type of FLT3 mutation, internal tandem duplication (FLT3-ITD), leads to localization in the endoplasmic reticulum and constitutive strong activation of STAT5. In contrast, the ligand-activated FLT3-wild type is mainly expressed on the cell surface and activates MAP kinases. Based on these backgrounds, several reports have demonstrated that glycosylation inhibitors are effective for inhibition of FLT3-ITD expression and intracellular localization. The general subcellular localization regulatory mechanisms for receptor tyrosine kinases are also discussed.

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“…In this review we will focus on gamma-secretase-dependent cleavage pathways. Other mechanisms of RTK processing have been recently reviewed elsewhere [5].…”

Section: Introductionmentioning

confidence: 99%

Gamma-secretase-dependent signaling of receptor tyrosine kinases

Merilahti

Elenius

2018

Oncogene

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Human genome harbors 55 receptor tyrosine kinases (RTK). At least half of the RTKs have been reported to be cleaved by gamma-secretase-mediated regulated intramembrane proteolysis. The two-step process involves releasing the RTK ectodomain to the extracellular space by proteolytic cleavage called shedding, followed by cleavage in the RTK transmembrane domain by the gamma-secretase complex resulting in release of a soluble RTK intracellular domain. This intracellular domain, including the tyrosine kinase domain, can in turn translocate to various cellular compartments, such as the nucleus or proteasome. The soluble intracellular domain may interact with transcriptional regulators and other proteins to induce specific effects on cell survival, proliferation, and differentiation, establishing an additional signaling mode for the cleavable RTKs. On the other hand, the same process can facilitate RTK turnover and proteasomal degradation. In this review we focus on the regulation of RTK shedding and gamma-secretase cleavage, as well as signaling promoted by the soluble RTK ICDs. In addition, therapeutic implications of increased knowledge on RTK cleavage on cancer drug development are discussed.

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Irreversible modifications of receptor tyrosine kinases

Cited by 21 publications

References 143 publications

Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor

Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor

Mutations of FLT3 receptor affect its surface glycosylation, intracellular localization, and downstream signaling

Gamma-secretase-dependent signaling of receptor tyrosine kinases

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