MET‐Activating Ubiquitin Multimers

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Abstract: Receptor tyrosine kinases (RTKs) are generally activated through their dimerization and/or oligomerization induced by their cognate ligands, and one such RTK hepatocyte growth factor (HGF) receptor, known as MET, plays an important role in tissue regeneration. Here we show the development of ubiquitin (Ub)‐based protein ligand multimers, referred to as U‐bodies, which act as surrogate agonists for MET and are derived from MET‐binding macrocyclic peptides. Monomeric Ub constructs (U‐body) were first generated by genetic implantation of a macrocyclic peptide pharmacophore into a structural loop of Ub (lasso‐grafting) and subsequent optimization of its flanking spacer sequences via mRNA display. Such U‐body constructs exhibit potent binding affinity to MET, thermal stability, and proteolytic stability. The U‐body constructs also partially/fully inhibited or enhanced HGF‐induced MET‐phosphorylation. Their multimerization to dimeric, tetrameric, and octameric U‐bodies linked by an appropriate peptide linker yielded potent MET activation activity and downstream cell proliferation‐promoting activity. This work suggests that lasso‐grafting of macrocycles to Ub is an effective approach to devising protein‐based artificial RTK agonists and it can be useful in the development of a new class of biologics for various therapeutic applications.

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Bibliographic citation: MET‐Activating Ubiquitin Multimers ; day:31 ; month:07 ; year:2023 ; extent:11
Angewandte Chemie / International edition. International edition ; (31.07.2023) (gesamt 11)

Creator: Kawakami, Naoya
Sato, Hiroki
Terasaka, Naohiro
Matsumoto, Kunio
Suga, Hiroaki

DOI: 10.1002/anie.202307157

URN: urn:nbn:de:101:1-2023073115151172957091

Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 14.08.2025, 11:01 AM CEST

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Kawakami, Naoya
Sato, Hiroki
Terasaka, Naohiro
Matsumoto, Kunio
Suga, Hiroaki

Other Objects (12)

MET‐Activating Ubiquitin Multimers

MET‐Activating Ubiquitin Multimers

Activating the ubiquitin family : UBA6 challenges the field

Activating the ubiquitin family : UBA6 challenges the field

Formation of the Alarmones Diadenosine Triphosphate and Tetraphosphate by Ubiquitin- and Ubiquitin-like-Activating Enzymes

Formation of the Alarmones Diadenosine Triphosphate and Tetraphosphate by Ubiquitin- and Ubiquitin-like-Activating Enzymes

Functional and phylogenetic analysis of the ubiquitylation system in Caenorhabditis elegans: ubiquitin-conjugating enzymes, ubiquitin-activating enzymes, and ubiquitin-like proteins

Functional and phylogenetic analysis of the ubiquitylation system in Caenorhabditis elegans: ubiquitin-conjugating enzymes, ubiquitin-activating enzymes, and ubiquitin-like proteins

Activating the NFE2L1-ubiquitin-proteasome system by DDI2 protects from ferroptosis

Activating the NFE2L1-ubiquitin-proteasome system by DDI2 protects from ferroptosis

Conjugation of the Ubiquitin Activating Enzyme UBE1 with the Ubiquitin-Like Modifier FAT10 Targets It for Proteasomal Degradation

Conjugation of the Ubiquitin Activating Enzyme UBE1 with the Ubiquitin-Like Modifier FAT10 Targets It for Proteasomal Degradation

Knowing then defeating: Ubiquitin activating enzyme, a promising target for cancer therapy

Knowing then defeating: Ubiquitin activating enzyme, a promising target for cancer therapy

Activating mutation in MET oncogene in familial colorectal cancer

Activating mutation in MET oncogene in familial colorectal cancer

Profiling the Cross Reactivity of Ubiquitin with the Nedd8 Activating Enzyme by Phage Display

Profiling the Cross Reactivity of Ubiquitin with the Nedd8 Activating Enzyme by Phage Display

CREB5 promotes invasiveness and metastasis in colorectal cancer by directly activating MET

CREB5 promotes invasiveness and metastasis in colorectal cancer by directly activating MET

Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET

Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET

Knockdown of ubiquitin-like modifier-activating enzyme 2 promotes apoptosis of clear cell renal cell carcinoma cells

Knockdown of ubiquitin-like modifier-activating enzyme 2 promotes apoptosis of clear cell renal cell carcinoma cells

MET‐Activating Ubiquitin Multimers

MET‐Activating Ubiquitin Multimers

Activating the ubiquitin family : UBA6 challenges the field

Activating the ubiquitin family : UBA6 challenges the field

Formation of the Alarmones Diadenosine Triphosphate and Tetraphosphate by Ubiquitin- and Ubiquitin-like-Activating Enzymes

Formation of the Alarmones Diadenosine Triphosphate and Tetraphosphate by Ubiquitin- and Ubiquitin-like-Activating Enzymes

Functional and phylogenetic analysis of the ubiquitylation system in Caenorhabditis elegans: ubiquitin-conjugating enzymes, ubiquitin-activating enzymes, and ubiquitin-like proteins

Functional and phylogenetic analysis of the ubiquitylation system in Caenorhabditis elegans: ubiquitin-conjugating enzymes, ubiquitin-activating enzymes, and ubiquitin-like proteins

Activating the NFE2L1-ubiquitin-proteasome system by DDI2 protects from ferroptosis

Activating the NFE2L1-ubiquitin-proteasome system by DDI2 protects from ferroptosis

Conjugation of the Ubiquitin Activating Enzyme UBE1 with the Ubiquitin-Like Modifier FAT10 Targets It for Proteasomal Degradation

Conjugation of the Ubiquitin Activating Enzyme UBE1 with the Ubiquitin-Like Modifier FAT10 Targets It for Proteasomal Degradation

Knowing then defeating: Ubiquitin activating enzyme, a promising target for cancer therapy

Knowing then defeating: Ubiquitin activating enzyme, a promising target for cancer therapy

Activating mutation in MET oncogene in familial colorectal cancer

Activating mutation in MET oncogene in familial colorectal cancer

Profiling the Cross Reactivity of Ubiquitin with the Nedd8 Activating Enzyme by Phage Display

Profiling the Cross Reactivity of Ubiquitin with the Nedd8 Activating Enzyme by Phage Display

CREB5 promotes invasiveness and metastasis in colorectal cancer by directly activating MET

CREB5 promotes invasiveness and metastasis in colorectal cancer by directly activating MET

Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET

Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET

Knockdown of ubiquitin-like modifier-activating enzyme 2 promotes apoptosis of clear cell renal cell carcinoma cells

Knockdown of ubiquitin-like modifier-activating enzyme 2 promotes apoptosis of clear cell renal cell carcinoma cells

MET‐Activating Ubiquitin Multimers

MET‐Activating Ubiquitin Multimers

Activating the ubiquitin family : UBA6 challenges the field

Activating the ubiquitin family : UBA6 challenges the field

Formation of the Alarmones Diadenosine Triphosphate and Tetraphosphate by Ubiquitin- and Ubiquitin-like-Activating Enzymes

Formation of the Alarmones Diadenosine Triphosphate and Tetraphosphate by Ubiquitin- and Ubiquitin-like-Activating Enzymes

Functional and phylogenetic analysis of the ubiquitylation system in Caenorhabditis elegans: ubiquitin-conjugating enzymes, ubiquitin-activating enzymes, and ubiquitin-like proteins

Functional and phylogenetic analysis of the ubiquitylation system in Caenorhabditis elegans: ubiquitin-conjugating enzymes, ubiquitin-activating enzymes, and ubiquitin-like proteins

Activating the NFE2L1-ubiquitin-proteasome system by DDI2 protects from ferroptosis

Activating the NFE2L1-ubiquitin-proteasome system by DDI2 protects from ferroptosis

Conjugation of the Ubiquitin Activating Enzyme UBE1 with the Ubiquitin-Like Modifier FAT10 Targets It for Proteasomal Degradation

Conjugation of the Ubiquitin Activating Enzyme UBE1 with the Ubiquitin-Like Modifier FAT10 Targets It for Proteasomal Degradation

Knowing then defeating: Ubiquitin activating enzyme, a promising target for cancer therapy

Knowing then defeating: Ubiquitin activating enzyme, a promising target for cancer therapy

Activating mutation in MET oncogene in familial colorectal cancer

Activating mutation in MET oncogene in familial colorectal cancer

Profiling the Cross Reactivity of Ubiquitin with the Nedd8 Activating Enzyme by Phage Display

Profiling the Cross Reactivity of Ubiquitin with the Nedd8 Activating Enzyme by Phage Display

CREB5 promotes invasiveness and metastasis in colorectal cancer by directly activating MET

CREB5 promotes invasiveness and metastasis in colorectal cancer by directly activating MET

Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET

Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET

Knockdown of ubiquitin-like modifier-activating enzyme 2 promotes apoptosis of clear cell renal cell carcinoma cells

Knockdown of ubiquitin-like modifier-activating enzyme 2 promotes apoptosis of clear cell renal cell carcinoma cells

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