Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change

Gallagher, Ewen; Gao, Min; Liu, Yun‐Cai; Karin, Michael

doi:10.1073/pnas.0510664103

Cited by 246 publications

(257 citation statements)

References 30 publications

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“…Because phosphorylation of substrates by LATS1 normally inhibit their function and Itch displayed oncogenic function by degrading a variety of tumor suppressors, LATS1 may involve in the activation of multiple tumor suppressors, such as p73, by phosphorylating and inactivating Itch. Indeed, several recent studies also described a role for serine/ threonine or tyrosine kinases in modulating Itch E3 ubiquitin ligase activity through phosphorylation (31)(32)(33). Therefore, it will be very interesting to further explore whether LATS1 regulates other suppressor pathways through phosphorylation and negative regulation of Itch.…”

Section: Identification Of Itch As a Lats1-interacting Protein By Promentioning

confidence: 99%

Itch E3 ubiquitin ligase regulates large tumor suppressor 1 stability

Zhou

She

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

112

109

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The large tumor suppressor 1 (LATS1) is a serine/threonine kinase and tumor suppressor found down-regulated in a broad spectrum of human cancers. LATS1 is a central player of the emerging Hippo-LATS suppressor pathway, which plays important roles in cell proliferation, apoptosis, and stem cell differentiation. Despite the ample data supporting a role for LATS1 in tumor suppression, how LATS1 is regulated at the molecular level remains largely unknown. In this study, we have identified Itch, a HECT class E3 ubiquitin ligase, as a unique binding partner of LATS1. Itch can complex with LATS1 both in vitro and in vivo through the PPxY motifs of LATS1 and the WW domains of Itch. Significantly, we found that overexpression of Itch promoted LATS1 degradation by polyubiquitination through the 26S proteasome pathway. On the other hand, knockdown of endogenous Itch by shRNAs provoked stabilization of endogenous LATS1 proteins. Finally, through several functional assays, we also revealed that change of Itch abundance alone is sufficient for altering LATS1-mediated downstream signaling, negative regulation of cell proliferation, and induction of apoptosis. Taking these data together, our study identifies E3 ubiquitin ligase Itch as a unique negative regulator of LATS1 and presents a possibility of targeting LATS1/Itch interaction as a therapeutic strategy in cancer.

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Section: Identification Of Itch As a Lats1-interacting Protein By Promentioning

confidence: 99%

Itch E3 ubiquitin ligase regulates large tumor suppressor 1 stability

Zhou

She

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

112

109

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“…This may be due to a failure of Itch to inactivate the upstream kinase MKK4 (23), although because Itch also interacts with MEKK1 (24), which phosphorylates MKK4, and Akt can also indirectly affect Jnk signaling (25), there may be multiple effects. Jnk also phosphorylates and activates Itch, thus creating a feedback loop that should inhibit Jnk activation (26,27), but this is evidently insufficient to regulate Jnk in the absence of Ndfip1.…”

Section: Discussionmentioning

confidence: 99%

Regulation of PTEN/Akt and MAP kinase signaling pathways by the ubiquitin ligase activators Ndfip1 and Ndfip2

Mund

Pelham

2010

Proc. Natl. Acad. Sci. U.S.A.

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Ndfip1 and Ndfip2 are related endosomal membrane proteins that bind to and activate members of the Nedd4 family of E3 ubiquitin ligases. These ligases in turn affect receptor tyrosine kinase signaling by ubiquitinating several key components of the signaling pathways. Here we investigate the role of the Ndfip proteins in EGF signaling. We show that they associate with the EGF receptor and PTEN, and control the ubiquitination and abundance of PTEN, c-Cbl, and Src family kinases. Ndfip2, but not Ndfip1, also binds to and is phosphorylated by Src and Lyn, and can act as a scaffold for Src phosphorylation of Ndfip1 and potentially other substrates. Depletion of Ndfip1 inhibits Akt activation in EGF-stimulated HeLa cells, stimulates activation of Jnk, and enhances cell multiplication. Thus Ndfip1 and Ndfip2 are physically and functionally associated with multiple components of the EGF signaling cascade, and their levels modulate the relative output of different signaling pathways.

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“…16 Consistent with the concept of intramolecular modification, it appears that the self-ubiquitinating activity of ITCH and other HECT ligases like NEDD4-1, NEDD4-2, SMURF2, and WWP1, is regulated through intramolecular interactions that are modulated by modifications such as phosphorylation, and that involve the HECT domain. [17][18][19] In an attempt to decipher the biological role of self-ubiquitination, it was proposed that it serves to target the ligase for degradation, 11 which has been observed indeed as a means of negative feedback for Mdm2, 6,20 E6-AP, 21 CBL ligases, 22 and the substrate receptor subunits of CRL complexes. 23 Self-ubiquitination can occur in substrateindependent 24 (Figure 2a) and -dependent modes 22 ( Figure 2b).…”

Section: Degradation Of Ligases Via Self-catalyzed Ubiquitinationmentioning

confidence: 99%

Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms

2011

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Ubiquitin modification of many cellular proteins targets them for proteasomal degradation, but in addition can also serve non-proteolytic functions. Over the last years, a significant progress has been made in our understanding of how modification of the substrates of the ubiquitin system is regulated. However, little is known on how the ubiquitin system that is comprised of B1500 components is regulated. Here, we discuss how the biggest subfamily within the system, that of the E3 ubiquitin ligases that endow the system with its high specificity towards the numerous substrates, is regulated and in particular via self-regulation mediated by ubiquitin modification. Ligases can be targeted for degradation in a self-catalyzed manner, or through modification mediated by an external ligase(s). In addition, non-proteolytic functions of self-ubiquitination, for example activation of the ligase, of E3s are discussed. Cell Death and Differentiation (2011) 18, 1393-1402 doi:10.1038/cdd.2011; published online 4 March 2011One of the major roles of the covalent modification of cellular proteins by ubiquitin is signaling them for proteasomal degradation ( Figure 1). The first step of the modification is catalyzed by the ubiquitin-activating enzyme, E1, which generates a high-energy thiol ester intermediate that is subsequently transferred to the second enzyme, a ubiquitinconjugating enzyme, E2. The third step ascertains substrate specificity, and is catalyzed by one of the numerous (B650) ubiquitin ligases, E3s. Typically, it results in the formation of an isopeptide bond between the C-terminal Gly of ubiquitin and an e-NH 2 group of an internal Lys of the substrate. Less frequently, it can generate a linear peptide bond with the a-NH 2 group, a thiol ester bond with an internal Cys, or an ester bond with a Thr or Ser. The three-step cascade of reactions is repeated, where additional ubiquitin moieties are attached sequentially to one another in an isopeptide bond involving one of the seven internal Lys residues in the ubiquitin moiety, thus generating a polyubiquitin chain. Lys48-based chains serve as a signal for proteasomal degradation, whereas chains based on other internal Lys residues, or modification by single moiety(ies) can serve non-proteolytic functions.Ligases fall into two main families: RING (really interesting new gene) and HECT (homologous to the E6-AP carboxy terminus) domain-containing E3s. RING ligases serve as scaffolds that facilitate direct transfer of ubiquitin from the E2 to the target protein. HECT E3s contain an active Cys residue to which ubiquitin binds prior to its transfer to the substrate (Figure 1). There are B600 RING finger and B30 HECT ligases in humans. Smaller families of ligases (U-box, plant homology domain, and zinc finger) have also been described.An important problem relates to regulation of the ubiquitin system components, and in particular to that of the ligases that are the specific substrate-recognizing elements. 1,2 Phosphorylation of an E3 can activate the protein, such as the ca...

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Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change

Cited by 246 publications

References 30 publications

Itch E3 ubiquitin ligase regulates large tumor suppressor 1 stability

Itch E3 ubiquitin ligase regulates large tumor suppressor 1 stability

Regulation of PTEN/Akt and MAP kinase signaling pathways by the ubiquitin ligase activators Ndfip1 and Ndfip2

Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms

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