Protein–protein interactions of ASPP2: an emerging therapeutic target

Iosub-Amir, Anat; Friedler, Assaf

doi:10.1039/c4md00147h

Cited by 9 publications

(9 citation statements)

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“…We have previously shown that ASPP2 693–918 is intrinsically disordered and is involved in ASPP2 intramolecular interactions between the Pro-rich and Ank-SH3 domains that regulate various ASPP2 interactions with other proteins . Together, ASPP2 331–692 and ASPP2 693–918 comprise a vast intrinsically disordered region, connecting the structured termini of ASPP2 that mediate numerous interactions important for ASPP2 functions . That CagA evolved to interact with the intrinsically disordered regions of ASPP2 that mediate fewer (i.e., two) known interactions, and not the structured termini that mediate many known interactions, may be important for its function to inhibit transformed host cells from proceeding with their intended apoptotic program.…”

Section: Resultsmentioning

confidence: 99%

“…24 Together, ASPP2 331−692 and ASPP2 693−918 comprise a vast intrinsically disordered region, connecting the structured termini of ASPP2 that mediate numerous interactions important for ASPP2 functions. 8 That CagA evolved to interact with the intrinsically disordered regions of ASPP2 that mediate fewer (i.e., two) known interactions, and not the structured termini that mediate many known interactions, may be important for its function to inhibit transformed host cells from proceeding with their intended apoptotic program. This mode of interaction could enable ASPP2 to interact with p53, via its Ank-SH3 domain, without competing for CagA binding.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Impaired apoptosis can lead to cancer by enabling the survival of damaged cells. − Accordingly, the proteins and pathways that regulate apoptosis are targets for the development of cancer therapies. , One such protein is the apoptosis stimulating protein of p53-2 (ASPP2), which enhances the pro-apoptotic activity of p53 upon DNA damage or oncogenic stimuli. , ASPP2 binds the p53 core/DNA binding domain and enhances its transactivation function on promoters of numerous pro-apoptotic genes. − The TP53BP2 gene encodes two ASPP2 splicing variants: full-length ASPP2 (residues 1–1128) and the ASPP2 N-terminal truncated isoform, termed Bcl-2 binding protein (Bbp, residues 1–1005). ,, ASPP2 and Bbp are primarily cytoplasmic, , but Bbp is also localized, in part, within the mitochondria and induces apoptosis via the mitochondrial death pathway . Downregulation of ASPP2 levels has been observed in several types of cancers, , and ASPP2 downregulation frequently correlates with poor prognoses in cancer patients …”

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confidence: 99%

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An Intrinsically Disordered Region in the Proapoptotic ASPP2 Protein Binds to the Helicobacter pylori Oncoprotein CagA

Reingewertz¹,

Iosub-Amir

Bonsor³

et al. 2015

Biochemistry

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The leading risk factor for gastric cancer in humans is infection by Helicobacter pylori strains that express and translocate the oncoprotein CagA into host epithelial cells. Once inside host cells, CagA interacts with ASPP2, which specifically stimulates p53-mediated apoptosis and reverses its pro-apoptotic function to promote ASPP2-dependent degradation of p53. The X-ray crystal structure of a complex between the N-terminal domain of CagA and a 56-residue fragment of ASPP2, of which 22 residues were resolved, was recently described. Here, we present biochemical and biophysical analyses of the interaction between the additional regions of CagA and ASPP2 potentially involved in this interaction. Using size exclusion chromatography-multiangle laser light scattering, circular dichroism, and nuclear magnetic resonance analyses, we observed that the ASPP2 region spanning residues 331-692, which was not part of the ASPP2 fragment used for crystallization, is intrinsically disordered in its unbound state. By surface plasmon resonance analysis and isothermal titration calorimetry, we found that a portion of this disordered region in ASPP2, residues 448-692, binds to the N-terminal domain of CagA. We also measured the affinity of the complex between the ASPP2 fragment composed of residues 693-918 and inclusive of the fragment used for crystallization and CagA. Additionally, we mapped the binding regions between ASPP2 and CagA using peptide arrays, demonstrating interactions between CagA and numerous peptides distributed throughout the ASPP2 protein sequence. Our results identify previously uncharacterized regions distributed throughout the protein sequence of ASPP2 as determinants of CagA binding, providing mechanistic insight into apoptosis reprogramming by CagA and potential new drug targets for H. pylori-mediated gastric cancer.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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An Intrinsically Disordered Region in the Proapoptotic ASPP2 Protein Binds to the Helicobacter pylori Oncoprotein CagA

Reingewertz¹,

Iosub-Amir

Bonsor³

et al. 2015

Biochemistry

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“…The apoptosis-stimulating proteins of the p53 (ASPP) family, which are identified as regulators of the tumor suppression function of p53, is compose of three members, ASPP1, ASPP2, and iASPP [ 84 ]. ASPP2 binds to various proteins that regulate apoptosis, cell polarity, proliferation, and differentiation [ 85 , 86 ]. p53 is a member of a family of three proteins: p53, p63, and p73.…”

Section: Aspp2 In Endometriosis and Endometrial Cancermentioning

confidence: 99%

The Roles of Tricellular Tight Junction Protein Angulin-1/Lipolysis-Stimulated Lipoprotein Receptor (LSR) in Endometriosis and Endometrioid-Endometrial Carcinoma

Shimada

Kohno

Konno

et al. 2021

Cancers

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Tight junction proteins play roles beyond permeability barriers functions and control cell proliferation and differentiation. The relation between tight junctions and the signal transduction pathways affects cell growth, invasion and migration. Abnormality of tight junction proteins closely contributes to epithelial mesenchymal transition (EMT) and malignancy of various cancers. Angulin-1/lipolysis-stimulated lipoprotein receptor (LSR) forms tricellular contacts that has a barrier function. Downregulation of angulin-1/LSR correlates with the malignancy in various cancers, including endometrioid-endometrial carcinoma (EEC). These alterations have been shown to link to not only multiple signaling pathways such as Hippo/YAP, HDAC, AMPK, but also cell metabolism in ECC cell line Sawano. Moreover, loss of angulin-1/LSR upregulates claudin-1, and loss of apoptosis stimulating p53 protein 2 (ASPP2) downregulates angulin-1/LSR. Angulin-1/LSR and ASPP2 concentrate at both midbody and centrosome in cytokinesis. In EEC tissues, angulin-1/LSR and ASPP2 are reduced and claudin-2 is overexpressed during malignancy, while in the tissues of endometriosis changes in localization of angulin-1/LSR and claudin-2 are seen. This review highlights how downregulation of angulin-1/LSR promotes development of endometriosis and EEC and discusses about the roles of angulin-1/LSR and its related proteins, including claudins and ASPP2.

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“…The ASPP proteins interact with different apoptosis-related proteins such as the p53 protein family, Bcl2 and NFκB 2 7 13 20 21 22 23 24 . iASPP Pro interacts with iASPP Ank-SH3 in cells and phosphorylation of iASPP by B1/CDK1 on S84 and S113 inhibits this interaction 25 .…”

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confidence: 99%

Highly homologous proteins exert opposite biological activities by using different interaction interfaces

Amir

Rosmalen

Mayer

et al. 2015

Sci Rep

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We present a possible molecular basis for the opposite activity of two homologues proteins that bind similar ligands and show that this is achieved by fine-tuning of the interaction interface. The highly homologous ASPP proteins have opposite roles in regulating apoptosis: ASPP2 induces apoptosis while iASPP inhibits it. The ASPP proteins are regulated by an autoinhibitory interaction between their Ank-SH3 and Pro domains. We performed a detailed biophysical and molecular study of the Pro – Ank-SH3 interaction in iASPP and compared it to the interaction in ASPP2. We found that iASPP Pro is disordered and that the interaction sites are entirely different: iASPP Ank-SH3 binds iASPP Pro via its fourth Ank repeat and RT loop while ASPP2 Ank-SH3 binds ASPP2 Pro via its first Ank repeat and the n-src loop. It is possible that by using different moieties in the same interface, the proteins can have distinct and specific interactions resulting in differential regulation and ultimately different biological activities.

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Protein–protein interactions of ASPP2: an emerging therapeutic target

Abstract: ASPP2 induces apoptosis and is downregulated in many types of cancer, making it a promising target for anti-cancer drugs.

Cited by 9 publications

References 98 publications

An Intrinsically Disordered Region in the Proapoptotic ASPP2 Protein Binds to the Helicobacter pylori Oncoprotein CagA

An Intrinsically Disordered Region in the Proapoptotic ASPP2 Protein Binds to the Helicobacter pylori Oncoprotein CagA

The Roles of Tricellular Tight Junction Protein Angulin-1/Lipolysis-Stimulated Lipoprotein Receptor (LSR) in Endometriosis and Endometrioid-Endometrial Carcinoma

Highly homologous proteins exert opposite biological activities by using different interaction interfaces

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