CIB1 functions as a Ca
            <sup>2+</sup>
            -sensitive modulator of stress-induced signaling by targeting ASK1

Yoon, Kyoung Wan; Cho, Junho; Lee, Jae Keun; Kang, Young‐Hee; Chae, Ji Soo; Kim, Young Mok; Kim, Jeehyun; Kim, Min Jung; Kim, Sung Eun; Baik, Ja-Hyun; Naik, Ulhas P.; Cho, Ssang-Goo; Choi, Eui-Ju

doi:10.1073/pnas.0812259106

Cited by 67 publications

(59 citation statements)

References 39 publications

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“…The molecular mechanism behind this control is poorly understood, although it has been suggested that it involves the transcription factor osterix (26). As this manuscript was being prepared, a publication (27) showed that calcium and integrin binding protein (CIB), which we had previously identified as an interacting partner of Nbr1 (28), functions as a Ca 2+ -sensitive modulator of stress-induced signaling by targeting apoptosis signalregulating kinase 1 (ASK1), a MAPK kinase kinase in JNK and p38 MAPK signaling pathways, which may fit with the function of Nbr1 in regulating p38 MAPK activity. Furthermore, Nbr1 was recently shown to modulate FGF receptor signaling through interaction with Spred2 (29), and with its previously well-documented involvement in titin kinase signaling in muscle (30), Nbr1 is now becoming recognized as a regulator of diverse cellular kinase signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity

Whitehouse

Waters

Marchbank

et al. 2010

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

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Section: Discussionmentioning

confidence: 99%

Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity

Whitehouse

Waters

Marchbank

et al. 2010

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

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“…CIB1 is known to interact with a variety of kinases, including ASK1 (34). This fact is relevant because we and others have reported that cADPR synthesis in sea urchin eggs is activated by a cGMPdependent phosphorylation process (35,36).…”

Section: Visualization Of Intracellular Interaction Of Cd38 With Cib1mentioning

confidence: 92%

Cytosolic interaction of type III human CD38 with CIB1 modulates cellular cyclic ADP-ribose levels

Liu

Zhao

et al. 2017

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

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CD38 catalyzes the synthesis of the Ca 2+ messenger, cyclic ADP-ribose (cADPR). It is generally considered to be a type II protein with the catalytic domain facing outside. How it can catalyze the synthesis of intracellular cADPR that targets the endoplasmic Ca 2+ stores has not been resolved. We have proposed that CD38 can also exist in an opposite type III orientation with its catalytic domain facing the cytosol. Here, we developed a method using specific nanobodies to immunotarget two different epitopes simultaneously on the catalytic domain of the type III CD38 and firmly established that it is naturally occurring in human multiple myeloma cells. Because type III CD38 is topologically amenable to cytosolic regulation, we used yeast-two-hybrid screening to identify cytosolic Ca 2+ and integrinbinding protein 1 (CIB1), as its interacting partner. The results from immunoprecipitation, ELISA, and bimolecular fluorescence complementation confirmed that CIB1 binds specifically to the catalytic domain of CD38, in vivo and in vitro. Mutational studies established that the N terminus of CIB1 is the interacting domain. Using shRNA to knock down and Cas9/guide RNA to knock out CIB1, a direct correlation between the cellular cADPR and CIB1 levels was demonstrated. The results indicate that the type III CD38 is functionally active in producing cellular cADPR and that the activity is specifically modulated through interaction with cytosolic CIB1.CD38 | cyclic ADP-ribose | membrane topology | calcium signaling | CIB1 C yclic ADP-ribose (cADPR) is a second-messenger molecule regulating the endoplasmic Ca 2+ stores in a wide range of cells spanning three biological kingdoms (1-4). Equally widespread is the enzyme activity that cyclizes nicotinamide-adenine dinucleotide (NAD) to produce cADPR (5). The first fully characterized enzyme was the ADP-ribosyl cyclase, a small soluble protein in Aplysia (6). It was thus surprising that the soluble cyclase shows sequence homology with the carboxyl (C-) domain of a mammalian membrane protein, CD38, a surface antigen first identified in lymphocytes (7). Subsequent work shows that CD38 is indeed a novel enzyme catalyzing not only the synthesis of cADPR but its hydrolysis to ADP-ribose as well (8,9). Gene ablation studies establish that CD38 is the dominant enzyme in mammalian tissues responsible for metabolizing cADPR and is important in regulating diverse physiological functions, ranging from neutrophil chemotaxis to oxytocin release and insulin secretion (10-12).It is generally believed that CD38 is a type II protein with a single transmembrane segment and a short amino(N)-tail of 21 residues extending into the cytosol, whereas the major portion of the molecule, its catalytic C-domain, is facing outside (13). This membrane topology seems paradoxical to CD38 functioning as a signaling enzyme producing an intracellular messenger. A vesicular mechanism has been proposed, positing that CD38 can be endocytosed, together with transport proteins, into endolysosomes. The transporters can then...

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“…The 13 C, 2 H, 15 N-uniformly labeled sample was expressed and purified according to an established protocol (12), and this sample was used to acquire the backbone 1 7 -glucose; this sample was used to record the CIB1 backbone CPMG-relaxation dispersion spectra. The synthetic 26-residue ␣IIb peptide (Ac-LVLAMWKVGFFKRNRP-PLEEDDEEGQ-OH) is the same as used in earlier studies (12), and it corresponds to amino acids 983-1008 of the platelet integrin ␣IIb subunit, with Gln-1008 as the C-terminal residue.…”

Section: Methodsmentioning

confidence: 99%

Solution Structures of Ca2+-CIB1 and Mg2+-CIB1 and Their Interactions with the Platelet Integrin αIIb Cytoplasmic Domain

Huang

Ishida

Yamniuk

et al. 2011

Journal of Biological Chemistry

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The calcium-and integrin-binding protein 1 (CIB1) is a ubiquitous Ca 2؉ -binding protein and a specific binding partner for the platelet integrin ␣IIb cytoplasmic domain, which confers the key role of CIB1 in hemostasis. CIB1 is also known to be involved in apoptosis, embryogenesis, and the DNA damage response. In this study, the solution structures of both Ca 2؉ -CIB1 and Mg 2؉ -CIB1 were determined using solution-state NMR spectroscopy. The methyl groups of Ile, Leu, and Val were selectively protonated to compensate for the loss of protons due to deuteration. The solution structure of Ca 2؉ -CIB1 possesses smaller opened EF-hands in its C-domain compared with available crystal structures. Ca 2؉ -CIB1 and Mg 2؉ -CIB1 have similar structures, but the N-lobe of Mg 2؉ -CIB1 is slightly more opened than that of Ca 2؉ -CIB1. Additional NMR experiments, such as chemical shift perturbation and methyl group solvent accessibility as measured by a nitroxide surface probe, were carried out to further characterize the structures of Ca 2؉ -CIB1 and Mg 2؉ -CIB1 as well as their interactions with the integrin ␣IIb cytoplasmic domain. NMR measurements of backbone amide proton slow motion (microsecond to millisecond) dynamics confirmed that the C-terminal helix of Ca 2؉ -CIB1 is displaced upon ␣IIb binding. The EF-hand III of both Ca 2؉ -CIB1 and Mg 2؉ -CIB1 was identified to be directly involved in the interaction of CIB1 with ␣IIb. Together, these data illustrate that CIB1 behaves quite differently from related EF-hand regulatory calcium-binding proteins, such as calmodulin or neuronal calcium sensor proteins.The calcium-and integrin-binding protein 1 (CIB1) is a member of the regulatory Ca 2ϩ -binding helix-loop-helix or EFhand protein family (1). CIB1 is a ubiquitous 191-residue (22 kDa) protein with several functions in cell signaling (2, 3). CIB1 has been reported to interact with a number of protein targets, including the platelet integrin ␣IIb subunit (4), sphingosine kinase 1 (5), p21-activated kinase (6), apoptosis signal-regulating kinase (7), polo-like protein kinases (8), and a recently reported new target in the regulation of cardiac hypertrophy, calcineurin B (9). The interaction of CIB1 with the integrin ␣IIb subunit has been studied extensively (10 -13). The integrin ␣IIb subunit usually associates with the integrin ␤3 subunit, and the heterodimeric ␣IIb␤3 protein is involved in both so-called "inside-out" and "outside-in" signaling pathways (3). CIB1 is believed to be capable of specifically binding to the ␣IIb cytoplasmic domain and dissociating the ␣IIb␤3 dimer, which in turn triggers integrin activation (11,12). The interactions between Ca 2ϩ -CIB1 and a fragment of the integrin ␣IIb subunit (residues 983-1008, hereafter referred to as the ␣IIb peptide) have been suggested to mainly involve a hydrophobic pocket in the C-domain of Ca 2ϩ -CIB1 with a dissociation constant in the submicromolar range (10).The calcium-bound CIB1 (Ca 2ϩ -CIB1) structure consists of four helix-loop-helix (EF-hand) Ca 2ϩ -binding m...

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CIB1 functions as a Ca ²⁺ -sensitive modulator of stress-induced signaling by targeting ASK1

Cited by 67 publications

References 39 publications

Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity

Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity

Cytosolic interaction of type III human CD38 with CIB1 modulates cellular cyclic ADP-ribose levels

Solution Structures of Ca2+-CIB1 and Mg2+-CIB1 and Their Interactions with the Platelet Integrin αIIb Cytoplasmic Domain

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CIB1 functions as a Ca 2+ -sensitive modulator of stress-induced signaling by targeting ASK1

Cited by 67 publications

References 39 publications

Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity

Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity

Cytosolic interaction of type III human CD38 with CIB1 modulates cellular cyclic ADP-ribose levels

Solution Structures of Ca2+-CIB1 and Mg2+-CIB1 and Their Interactions with the Platelet Integrin αIIb Cytoplasmic Domain

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CIB1 functions as a Ca ²⁺ -sensitive modulator of stress-induced signaling by targeting ASK1