A phosphoinositide-binding sequence is shared by PH domain target molecules—a model for the binding of PH domains to proteins

Alberti, Saverio

doi:10.1002/(sici)1097-0134(19980401)31:1<1::aid-prot1>3.0.co;2-r

Cited by 26 publications

(24 citation statements)

References 43 publications

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“…5A). HIKE is a highly conserved sequence motif that selectively occurs in proteins that bind pleckstrin homology domains (47,48). HIKE was identified in strong PH-binding candidates such as G ␤ , protein kinase C, and Akt.…”

Section: Discussionmentioning

confidence: 99%

“…5A, that selectively occurs in proteins that bind PH domains (47). This motif was originally identified by sequence homology analysis of the proteins considered the strongest PH binding candidates, such as PKC and Akt (48). A conserved ␤ strand-loop-␤ strand structure is exhibited by HIKE, despite the fact that the proteins in which they are found have widely different threedimensional structures (48).…”

Section: Fig 3 the Ph Domain Of Ckip-1 Is Required For Interactionsmentioning

confidence: 99%

“…This motif was originally identified by sequence homology analysis of the proteins considered the strongest PH binding candidates, such as PKC and Akt (48). A conserved ␤ strand-loop-␤ strand structure is exhibited by HIKE, despite the fact that the proteins in which they are found have widely different threedimensional structures (48). There is a highly conserved acidic residue 8 amino acids downstream from the most C-terminal conserved Lysine.…”

Section: Fig 3 the Ph Domain Of Ckip-1 Is Required For Interactionsmentioning

confidence: 99%

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The Pleckstrin Homology Domain of CK2 Interacting Protein-1 Is Required for Interactions and Recruitment of Protein Kinase CK2 to the Plasma Membrane

Olsten¹,

Canton²,

Zhang³

et al. 2004

Journal of Biological Chemistry

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CKIP-1 is a recently identified interaction partner of protein kinase CK2 with a number of protein-protein interaction motifs, including an N-terminal pleckstrin homology domain. To test the hypothesis that CKIP-1 has a role in targeting CK2 to specific locations, we examined the effects of CKIP-1 on the localization of CK2. These studies demonstrated that CKIP-1 can recruit CK2 to the plasma membrane. Furthermore, the pleckstrin homology domain of CKIP-1 was found to be required for interactions with CK2 and for the recruitment of CK2 to the plasma membrane. In this regard, point mutations in this domain abolish membrane localization and compromise interactions with CK2. In addition, replacement of the pleckstrin homology domain with a myristoylation signal was insufficient to elicit any interaction with CK2. An investigation of the lipid binding of CKIP-1 reveals that it has broad specificity. A comparison with other pleckstrin homology domains revealed that the pleckstrin homology domain of CKIP-1 is distinct from other defined classes of pleckstrin homology domains. Finally, examination of CK2␣ for a region that mediates interactions with CKIP-1 revealed a putative HIKE domain, a complex motif found exclusively in proteins that bind pleckstrin homology domains. However, mutations within this motif were not able to abolish CKIP-1-CK2 interactions suggesting that this motif by itself may not be sufficient to mediate interactions. Overall, these results provide novel insights into how CK2, a predominantly nuclear enzyme, is targeted to the plasma membrane, and perhaps more importantly how it may be regulated. CK21 (formerly casein kinase II) is a ubiquitously expressed extraordinary conserved Ser/Thr kinase found in all eukaryotic cells (1-3). CK2 has been shown to be essential for viability in a variety of models ranging from yeast to mammalian cells (4 -6). An elevated CK2 activity has been detected in leukemic cells, healthy tissues with high mitotic index, and in a variety of human cancers (7-9). In addition, CK2 exhibits oncogenic activity when overexpressed in transgenic mice (10). The majority of CK2 is found in the nucleus of logarithmically growing cells (11-13); however, there have been indications that the nuclear/cytoplasmic distribution of CK2 is regulated in a cell cycle-dependent manner (14). Antibodies that interfere with the nuclear uptake of CK2 inhibit mitogenic stimulation upon micro-injection into cells (15), indicating the importance of the nature of CK2 localization for its biological function. To date, CK2 has been shown to phosphorylate and/or interact with a broad range of proteins located in a variety of cellular compartments, including nuclear proteins (16 -20), cytoplasmic proteins (21-23), and proteins localized at the plasma membrane (24 -26).This tetrameric enzyme is composed of two catalytic (␣ and ␣Ј) and two regulatory subunits (␤). The two catalytic subunits are products of separate genes and show greater than 90% sequence identity over their N-terminal 330 amino acids (27). ...

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Section: Discussionmentioning

confidence: 99%

Section: Fig 3 the Ph Domain Of Ckip-1 Is Required For Interactionsmentioning

confidence: 99%

Section: Fig 3 the Ph Domain Of Ckip-1 Is Required For Interactionsmentioning

confidence: 99%

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The Pleckstrin Homology Domain of CK2 Interacting Protein-1 Is Required for Interactions and Recruitment of Protein Kinase CK2 to the Plasma Membrane

Olsten¹,

Canton²,

Zhang³

et al. 2004

Journal of Biological Chemistry

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“…This prevents the binding of the AKT PH to plasma membrane phospholipids (42) and of the AKT kinase domain to its substrates, thus specifically inhibiting AKT activity (Supplementary Table S2E; Supplementary Fig. S2B).…”

Section: Trop-2 Determines Tumor Response To Akt Inhibitorsmentioning

confidence: 99%

Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors

Guerra

Trerotola

Tripaldi

et al. 2016

Clinical Cancer Research

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Purpose: Inhibition of AKT is a key target area for personalized cancer medicine. However, predictive markers of response to AKT inhibitors are lacking. Correspondingly, the AKT-dependent chain of command for tumor growth, which will mediate AKTdependent therapeutic responses, remains unclear.Experimental Design: Proteomic profiling was utilized to identify nodal hubs of the Trop-2 cancer growth-driving network. Kinase-specific inhibitors were used to dissect Trop-2-dependent from Trop-2-independent pathways. In vitro assays, in vivo preclinical models, and case series of primary human breast cancers were utilized to define the mechanisms of Trop-2-driven growth and the mode of action of Trop-2-predicted AKT inhibitors.Results: Trop-2 and AKT expression was shown to be tightly coordinated in human breast cancers, with virtual overlap with AKT activation profiles at T308 and S473, consistent with functional interaction in vivo. AKT allosteric inhibitors were shown to only block the growth of Trop-2-expressing tumor cells, both in vitro and in preclinical models, being ineffective on Trop-2-null cells. Consistently, AKTtargeted siRNA only impacted on Trop-2-expressing cells. Lentiviral downregulation of endogenous Trop-2 abolished tumor response to AKT blockade, indicating Trop-2 as a mandatory activator of AKT.Conclusions: Our findings indicate that the expression of Trop-2 is a stringent predictor of tumor response to AKT inhibitors. They also support the identification of target-activatory pathways, as efficient predictors of response in precision cancer therapy. Clin Cancer Res; 22(16); 4197-205. Ó2016 AACR.

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“…In addition, given the structural similarities of these domains, some PH domains might bind specific peptide sequences at the site PTB and FERM domains use. A protein interaction site at this location has been suggested on the basis of theoretical considerations (Alberti, 1998). Such peptide sequences might belong to the cytoplasmic regions of integral membrane proteins, which would explain the difficulties in identifying protein binding partners for PH domains in yeast two-hybrid screens.…”

Section: Ph- Ptb-and Ferm Domainsmentioning

confidence: 99%

Inositol-lipid binding motifs: signal integrators through protein-lipid and protein-protein interactions

Balla

2005

Journal of Cell Science

231

235

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Inositol lipids have emerged as universal lipid regulators of protein signaling complexes in defined membrane compartments. The number of protein modules that are known to recognise these membrane lipids is rapidly increasing. Pleckstrin homology domains, FYVE domains, PX domains, ENTH domains, CALM domains, PDZ domains, PTB domains and FERM domains are all inositide-recognition modules. The latest additions to this list are members of the clathrin adaptor protein and arrestin families. Initially, inositol lipids were believed to recruit signaling molecules to specific membrane compartments, but many of the domains clearly do not possess high enough affinity to act alone as localisation signals. Another important notion is that some (and probably most) of these protein modules also have protein binding partners, and their protein- and lipid-binding activities might influence one another through allosteric mechanisms. Comparison of the structural features of these domains not only reveals a high degree of conservation of their lipid interaction sites but also highlights their evolutionary link to protein modules known for protein-protein interactions. Protein-protein interactions involving lipid-binding domains could serve as the basis for phosphoinositide-induced conformational regulation of target proteins at biological membranes. Therefore, these modules function as crucially important signal integrators, which explains their involvement in a broad range of regulatory functions in eukaryotic cells.

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A phosphoinositide-binding sequence is shared by PH domain target molecules—a model for the binding of PH domains to proteins

Cited by 26 publications

References 43 publications

The Pleckstrin Homology Domain of CK2 Interacting Protein-1 Is Required for Interactions and Recruitment of Protein Kinase CK2 to the Plasma Membrane

The Pleckstrin Homology Domain of CK2 Interacting Protein-1 Is Required for Interactions and Recruitment of Protein Kinase CK2 to the Plasma Membrane

Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors

Inositol-lipid binding motifs: signal integrators through protein-lipid and protein-protein interactions

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