Cortical dynamics during cell motility are regulated by CRL3KLHL21 E3 ubiquitin ligase

Courthéoux, Thibault; Enchev, Radoslav I.; Lampert, Fabienne; Gerez, Juan; Beck, Jochen; Picotti, Paola; Sumara, Izabela; Peter, Matthias

doi:10.1038/ncomms12810

Cited by 21 publications

(25 citation statements)

References 43 publications

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“…Furthermore, the identity of such E3 ligases mediating selective autophagy in focal adhesion turnover remains elusive. In light of recent findings, one tempting candidate may be a member of the cullin-RING ligases (CRL) recently implicated in mediating both focal adhesions as well as autophagy [111, 112]. CRL3 has recently been localized to focal adhesion structures at the cell leading edge and demonstrated to promote cell migration by ubiquitinating the microtubule interacting protein, EB1 [112].…”

Section: Autophagy Dependent Regulation Of Focal Adhesion Dynamicsmentioning

confidence: 99%

“…In light of recent findings, one tempting candidate may be a member of the cullin-RING ligases (CRL) recently implicated in mediating both focal adhesions as well as autophagy [111, 112]. CRL3 has recently been localized to focal adhesion structures at the cell leading edge and demonstrated to promote cell migration by ubiquitinating the microtubule interacting protein, EB1 [112]. Highlighting the importance of CRL proteins in mediating focal adhesion dynamics, cells with decreased activity of the CRL3 KLHL21 ligase or non-ubiquitinated EB1 are unable to migrate as they exhibit defects in focal adhesion dynamics and in the formation of lamellipodia [112].…”

Section: Autophagy Dependent Regulation Of Focal Adhesion Dynamicsmentioning

confidence: 99%

“…CRL3 has recently been localized to focal adhesion structures at the cell leading edge and demonstrated to promote cell migration by ubiquitinating the microtubule interacting protein, EB1 [112]. Highlighting the importance of CRL proteins in mediating focal adhesion dynamics, cells with decreased activity of the CRL3 KLHL21 ligase or non-ubiquitinated EB1 are unable to migrate as they exhibit defects in focal adhesion dynamics and in the formation of lamellipodia [112]. Additionally, CRL proteins have been linked to autophagy via the targeted degradation of a number of autophagy regulators including DAPK, which regulates the dissociation of Beclin-1 from Bcl-2; Atg14L, which is involved in autophagosome initiation; and the ULK1 substrate Ambra1, which associates with other CRL proteins to promote autophagy by suppressing mTORC1 [111, 113–116].…”

Section: Autophagy Dependent Regulation Of Focal Adhesion Dynamicsmentioning

confidence: 99%

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The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion

Vlahakis

Debnath

2017

Journal of Molecular Biology

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Autophagy is a cellular degradation process integral for promoting cellular adaptation during metabolic stress while also functioning as a cellular homeostatic mechanism. Mounting evidence also demonstrates that autophagy is induced upon loss of integrin-mediated cell attachments to the surrounding extracellular matrix (ECM). Analogous to its established cytoprotective role during nutrient starvation, autophagy protects cells from detachment-induced cell death, termed anoikis. Here, we review the significance of autophagy as an anoikis resistance pathway, focusing on the intracellular signals associated with integrins that modulate the autophagy response and dictate the balance between cell death and survival following loss of cell-matrix contact. In addition, we highlight recent studies demonstrating that autophagy functions in the upstream regulation of integrin-mediated cell adhesion via the control of focal adhesion remodeling, and discuss how these emerging interconnections between integrin-mediated adhesion pathways and autophagy influence cancer progression and metastasis.

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Section: Autophagy Dependent Regulation Of Focal Adhesion Dynamicsmentioning

confidence: 99%

Section: Autophagy Dependent Regulation Of Focal Adhesion Dynamicsmentioning

confidence: 99%

Section: Autophagy Dependent Regulation Of Focal Adhesion Dynamicsmentioning

confidence: 99%

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The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion

Vlahakis

Debnath

2017

Journal of Molecular Biology

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“…Apart from KLHL20, there are additional adaptors possibly playing carcinogenic roles largely based of pathological evidence. KLHL21, an adaptor regulating cell mitosis and migration [145,146], is abnormally overexpressed in hepatocellular carcinoma tissues [147]. Meanwhile, KLHL42 is also believed to regulate mitotic progression and is overexpressed in T-cell lymphoma [148,149].…”

Section: Other Cul3-based Oncogenic E3mentioning

confidence: 99%

Functional analysis of Cullin 3 E3 ligases in tumorigenesis

Cheng

Guo

Wang

et al. 2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Cullin 3-RING ligases (CRL3) play pivotal roles in the regulation of various physiological and pathological processes, including neoplastic events. The substrate adaptors of CRL3 typically contain a BTB domain that mediates the interaction between Cullin 3 and target substrates to promote their ubiquitination and subsequent degradation. The biological implications of CRL3 adaptor proteins have been well described where they have been found to play a role as either an oncogene, tumor suppressor, or can mediate either of these effects in a context-dependent manner. Among the extensively studied CRL3-based E3 ligases, the role of the adaptor protein SPOP (speckle type BTB/POZ protein) in tumorigenesis appears to be tissue or cellular context dependent. Specifically, SPOP acts as a tumor suppressor via destabilizing downstream oncoproteins in many malignancies, especially in prostate cancer. However, SPOP has largely an oncogenic role in kidney cancer. Keap1, another well-characterized CRL3 adaptor protein, likely serves as a tumor suppressor within diverse malignancies, mainly due to its specific turnover of its downstream oncogenic substrate, NRF2 (nuclear factor erythroid 2-related factor 2). In accordance with the physiological role the various CRL3 adaptors exhibit, several pharmacological agents have been developed to disrupt its E3 ligase activity, therefore blocking its potential oncogenic activity to mitigate tumorigenesis.

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“…Since then, ubiquitin modification has been increasingly recognized as an important regulator of the dynamic microtubule network. In HeLa cells, the Cul3‐KLHL21 E3 ligase complex controls cell migration due to its ability to ubiquitinate MT‐interacting CH‐domains of end binding protein 1 (EB1) which regulates MT plus‐end growth (Courtheoux et al, ). Tubulin‐folding cofactor B (TBCB) plays an important role in microtubule biosynthesis together with tubulin‐folding cofactor E (TBCE), and its regulatory function can be adjusted by ubiquitin‐mediated proteolysis.…”

Section: Ubiquitination In Cellular Events Of Epithelial Morphogenesismentioning

confidence: 99%

Degradation for better survival? Role of ubiquitination in epithelial morphogenesis

Cheng

Zheng

et al. 2018

Biological Reviews

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As a prevalent post-translational modification, ubiquitination is essential for many developmental processes. Once covalently attached to the small and conserved polypeptide ubiquitin (Ub), a substrate protein can be directed to perform specific biological functions via its Ub-modified form. Three sequential catalytic reactions contribute to this process, among which E3 ligases serve to identify target substrates and promote the activated Ub to conjugate to substrate proteins. Ubiquitination has great plasticity, with diverse numbers, topologies and modifications of Ub chains conjugated at different substrate residues adding a layer of complexity that facilitates a huge range of cellular functions. Herein, we highlight key advances in the understanding of ubiquitination in epithelial morphogenesis, with an emphasis on the latest insights into its roles in cellular events involved in polarized epithelial tissue, including cell adhesion, asymmetric localization of polarity determinants and cytoskeletal organization. In addition, the physiological roles of ubiquitination are discussed for typical examples of epithelial morphogenesis, such as lung branching, vascular development and synaptic formation and plasticity. Our increased understanding of ubiquitination in epithelial morphogenesis may provide novel insights into the molecular mechanisms underlying epithelial regeneration and maintenance.

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Cortical dynamics during cell motility are regulated by CRL3KLHL21 E3 ubiquitin ligase

Cited by 21 publications

References 43 publications

The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion

The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion

Functional analysis of Cullin 3 E3 ligases in tumorigenesis

Degradation for better survival? Role of ubiquitination in epithelial morphogenesis

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