Identification of a PGXPP degron motif in dishevelled and structural basis for its binding to the E3 ligase KLHL12

Chen, Zhuoyao; Wasney, Gregory A.; Picaud, S.; Filippakopoulos, P.; Vedadi, Masoud; D’Angiolella, Vincenzo; Bullock, Alex N.

doi:10.1101/2020.02.12.945758

Cited by 4 publications

(3 citation statements)

References 43 publications

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“…In principle, small-molecule ligands could be developed to target the phosphoinositide binding site of the PH domain (65)(66)(67) or disrupt interactions between the proline-rich domain and KLHL12 (68) or homotypic interactions involved in oligomerization and cluster formation (69). Further, ligands that bind to PLEKHA4 but do not disrupt function could still serve as starting points for development of PROTACs/degraders (70,71).…”

Section: Discussionmentioning

confidence: 99%

PLEKHA4 Promotes Wnt/β-Catenin Signaling–Mediated G1–S Transition and Proliferation in Melanoma

et al. 2021

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Despite recent promising advances in targeted therapies and immunotherapies, patients with melanoma incur substantial mortality. In particular, inhibitors targeting BRAF-mutant melanoma can lead to resistance, and no targeted therapies exist for NRAS-mutant melanoma, motivating the search for additional therapeutic targets and vulnerable pathways. Here we identify a regulator of Wnt/β-catenin signaling, PLEKHA4, as a factor required for melanoma proliferation and survival. PLEKHA4 knockdown in vitro decreased Dishevelled levels, attenuated Wnt/β-catenin signaling, and blocked progression through the G1–S cell-cycle transition. In mouse xenograft and allograft models, inducible PLEKHA4 knockdown attenuated tumor growth in BRAF- and NRAS-mutant melanomas and exhibited an additive effect with the clinically used inhibitor encorafenib in a BRAF-mutant model. As an E3 ubiquitin ligase regulator with both lipid- and protein-binding partners, PLEKHA4 presents several opportunities for targeting with small molecules. Our work identifies PLEKHA4 as a promising drug target for melanoma and clarifies a controversial role for Wnt/β-catenin signaling in the control of melanoma proliferation. Significance: This study establishes that melanoma cell proliferation requires the protein PLEKHA4 to promote pathologic Wnt signaling for proliferation, highlighting PLEKHA4 inhibition as a new avenue for the development of targeted therapies.

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Section: Discussionmentioning

confidence: 99%

PLEKHA4 Promotes Wnt/β-Catenin Signaling–Mediated G1–S Transition and Proliferation in Melanoma

et al. 2021

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“…The crystal structure of KLHDC2 in complex with C-terminal diglycine degrons of early terminated selenoproteins SelK and SelS, and N-terminal proteolytic fragment of USP1 reveals a deep and basic pocket at the centre of the Kelch domain of KLHDC2 that recognises the substrate via a network of hydrogen bonding interactions with its terminal carboxyl group, achieving nanomolar binding affinities (Figure 2c) [24]. 2d) [26,27]. The structures reveal a U-shaped turn conformation of bound substrates in the KLHL12 hydrophobic pocket.…”

Section: Substrate Recognition By E3 Ligase Substrate Receptorsmentioning

confidence: 99%

“…SOCS2 utilises the SH2 domain to recognise phosphodegrons from erythropoietin receptor (EpoR) and growth hormone receptor (GHR) (Figure 2h) [32 ]. Unlike in SOCS3 and SOCS6 where the BG loop closes-in over the substrate to form a hydrophobic channel, the loop in [27]). (e) DAPK1 (cyan) forming a loose helical turn while interacting with KLHL20 (PDB: 6GY5 [28]).…”

Section: Substrate Recognition By E3 Ligase Substrate Receptorsmentioning

confidence: 99%

Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues

Ramachandran

Ciulli

2021

Current Opinion in Structural Biology

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PLEKHA4 Promotes Wnt/β-catenin Signaling-Mediated G1/S Transition and Proliferation in Melanoma

Shah

Cao

White

et al. 2020

Preprint

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Melanoma patients incur substantial mortality, despite promising recent advances in targeted therapies and immunotherapies. In particular, inhibitors targeting BRAF-mutant melanoma can lead to resistance, and no targeted therapies exist for NRAS-mutant melanoma, motivating the search for additional therapeutic targets and vulnerable pathways. Here, we identify a regulator of Wnt/β-catenin signaling, PLEKHA4, as a factor required for melanoma proliferation and survival. PLEKHA4 knockdown in vitro leads to lower Dishevelled levels, attenuated Wnt/β-catenin signaling, and a block of progression through the G1/S cell cycle transition. In mouse xenograft models, inducible PLEKHA4 knockdown attenuated tumor growth in BRAF- and NRAS-mutant melanomas and synergized with the clinically used inhibitor encorafenib in a BRAF-mutant model. As an E3 ubiquitin ligase regulator with both lipid and protein binding partners, PLEKHA4 presents several opportunities for targeting with small molecules. Our work identifies PLEKHA4 as a promising drug target for melanoma and clarifies a controversial role for Wnt/β-catenin signaling in the control of melanoma proliferation.

show abstract

Identification of a PGXPP degron motif in dishevelled and structural basis for its binding to the E3 ligase KLHL12

Cited by 4 publications

References 43 publications

PLEKHA4 Promotes Wnt/β-Catenin Signaling–Mediated G1–S Transition and Proliferation in Melanoma

PLEKHA4 Promotes Wnt/β-Catenin Signaling–Mediated G1–S Transition and Proliferation in Melanoma

Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues

PLEKHA4 Promotes Wnt/β-catenin Signaling-Mediated G1/S Transition and Proliferation in Melanoma

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