A Myristoylated Calcium-binding Protein that Preferentially Interacts with the Alzheimer's Disease Presenilin 2 Protein

Stabler, Stacy M.; Ostrowski, Lisa L.; Janicki, Susan M.; Monteiro, Mervyn J.

doi:10.1083/jcb.145.6.1277

Cited by 129 publications

(156 citation statements)

References 81 publications

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“…CIB1 contains two canonical Ca 2ϩ -binding EFhand motifs in the COOH-terminal globular domain (12,13). Although it was initially discovered in platelets as a protein that interacts with integrin ␣ IIb (11), CIB1 also binds many other proteins including presenilin 2, DNA-dependent protein kinase, the polo-like kinases Fnk and Snk (14)(15)(16). Furthermore, the binding of Ca 2ϩ to CIB1 induces conformational changes that modulate the interaction with at least some of its binding proteins (17).…”

mentioning

confidence: 99%

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

Yoon¹,

Cho²,

Lee³

et al. 2009

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

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Calcium and integrin binding protein 1 (CIB1) is a Ca 2+ -binding protein of 22 kDa that was initially identified as a protein that interacts with integrin α IIb . Although it interacts with various proteins and has been implicated in diverse cellular functions, the molecular mechanism by which CIB1 regulates intracellular signaling networks has remained unclear. We now show that, by targeting apoptosis signal-regulating kinase 1 (ASK1), CIB1 negatively regulates stress-activated MAPK signaling pathways. CIB1 was thus shown to bind to ASK1, to interfere with the recruitment of TRAF2 to ASK1, and to inhibit the autophosphorylation of ASK1 on threonine-838, thereby blocking ASK1 activation. Furthermore, CIB1 mitigated apoptotic cell death initiated either by TNF-α in breast cancer MCF7 cells or by 6-hydroxydopamine (6-OHDA) in dopaminergic cells. Ca 2+ influx induced by membrane depolarization reversed the inhibitory effect of CIB1 on 6-OHDA-induced ASK1 activation and cell death in dopaminergic neurons. These observations thus suggest that CIB1 functions as a Ca 2+ -sensitive negative regulator of ASK1-mediated signaling events.

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mentioning

confidence: 99%

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

Yoon¹,

Cho²,

Lee³

et al. 2009

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

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“…Snk and Fnk are activated by progesterone in maturing frog oocytes (68) and have roles in both G 1 and mitotic phases of the cell cycle, and CIB could affect the activity of these kinases. CIB is found in both the nucleus and cytoplasm, and its subcellular localization can be influenced by association with its interacting partners and by calcium levels (52,67), but its role in the nucleus is unexplored. Interaction with DNA PK would implicate CIB in the response to DNA double strand break sensing and repair.…”

Section: Discussionmentioning

confidence: 99%

EDD, the Human Hyperplastic Discs Protein, Has a Role in Progesterone Receptor Coactivation and Potential Involvement in DNA Damage Response

Henderson¹,

Russell²,

Hird³

et al. 2002

Journal of Biological Chemistry

100

131

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The ubiquitin-protein ligase EDD encodes an orthologue of the hyperplastic discs tumor suppressor gene, which has a critical role in Drosophila development. Frequent allelic imbalance at the EDD chromosomal locus in human cancers suggests a role in tumorigenesis. In addition to a HECT (homologous to E6-AP carboxyl terminus) domain, the EDD protein contains a UBR1 zinc finger motif and ubiquitin-associated domain, each of which indicates involvement in ubiquitinylation pathways. This study shows that EDD interacts with importin ␣5 through consensus basic nuclear localization signals and is localized in cell nuclei. EDD also binds progesterone receptor (PR) and potentiates progestin-mediated gene transactivation. This activity is comparable with that of the coactivator SRC-1, but, in contrast, the interaction between EDD and PR does not appear to involve an LXXLL receptor-binding motif. EDD also binds calcium-and integrin-binding protein/ DNA-dependent protein kinase-interacting protein, a potential target of ubiquitin-mediated proteolysis, and an altered association is found between EDD and calcium-and integrin-binding protein/DNA-dependent protein kinase-interacting protein in response to DNA damage. The data presented here demonstrate a role for EDD in PR signaling but also suggest a link to cancer through DNA damage response pathways.The EDD gene, the apparent human orthologue of the Drosophila melanogaster gene "hyperplastic discs" (hyd), was originally isolated as a progestin-induced gene (1). Some mutations in hyd result in hyperplasia of larval imaginal discs, suggesting hyd functions as a tumor suppressor gene. The proposed function of the HYD protein in Drosophila in initiation, maintenance, and/or termination of cell proliferation (2) points to a pivotal role in coordinating the balance between cell cycle progression and differentiation. Many pathways controlling these processes are highly conserved through evolution, and consequently mutations in orthologous genes can have hyperplastic or tumorigenic effects in both mammals and Drosophila. Notch gene mutations, for example, result in hyperplasia of the embryonic nervous system in Drosophila and have also been linked to human leukemia and breast cancer (3), whereas the Patched gene product is required for correct Drosophila development and if mutated in humans causes developmental abnormalities together with predisposition to basal cell carcinoma (4). Similarly, tumors are produced in both Drosophila and mice upon deletion of the large tumor suppressor gene (lats) (5). Based on these precedents, recent studies have sought to determine the normal biological functions of EDD and whether it has a role in human cancer (1, 6). 1Although the cellular functions of the EDD and HYD proteins are unknown, significant homology exists between their carboxyl termini and those of E6-AP and related proteins (7, 8). These HECT 2 (for homologous to E6-AP carboxyl terminus) family proteins form a subclass of ubiquitin-protein ligases (E3 enzymes) playing a role in the ubi...

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“…Some PS-associated proteins (e.g. calpain, calmyrin, and sorcin) also bind calcium, and PS has been implicated in intracellular calcium homeostasis (27,(47)(48)(49)(50)(51). In this regard, CALP might have a function in PS-mediated calcium modulation.…”

Section: Effect Of the Overexpression Of Calp On Metabolism Of Ps Polmentioning

confidence: 99%

Molecular Cloning and Characterization of CALP/KChIP4, a Novel EF-hand Protein Interacting with Presenilin 2 and Voltage-gated Potassium Channel Subunit Kv4

Morohashi¹,

Hatano²,

Ohya³

et al. 2002

Journal of Biological Chemistry

150

122

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Presenilin (PS) genes linked to early-onset familialAlzheimer's disease encode polytopic membrane proteins that are presumed to constitute the catalytic subunit of ␥-secretase, forming a high molecular weight complex with other proteins. During our attempts to identify binding partners of PS2, we cloned CALP (calsenilin-like protein)/KChIP4, a novel member of calsenilin/ KChIP protein family that interacts with the C-terminal region of PS. Upon co-expression in cultured cells, CALP was directly bound to and co-localized with PS2 in endoplasmic reticulum. Alzheimer's disease (AD)1 is a progressive dementing neurodegenerative disorder characterized by a massive deposition of ␤-amyloid and tau-rich neurofibrillary lesions in the brains (reviewed in Ref. 1 and references therein). A subset of AD is inherited as an autosomal dominant trait, and mutations in three different genes have thus far been linked to early-onset autosomal dominant forms of familial AD (FAD). Among these, presenilin 1 (PS1) and PS2 account for the majority of the early onset FAD (1). PS1 and PS2 genes encode polytopic integral membrane proteins that are predominantly localized in intracellular membranes and span the membrane six to eight times.PS proteins undergo endoproteolysis to give rise to N-and C-terminal fragments, which are the preponderant forms of endogenous PS in vivo (2). These fragments form a heterodimer and are incorporated into high molecular weight (HMW) protein complexes (2-5) that are highly stabilized (t1 ⁄2 ϭ ϳ20 h; Ref.6), whereas holoproteins of PS are rapidly degraded (t1 ⁄2 ϭ ϳ2 h) (6, 7). The steady-state levels of PS fragments seem to be tightly regulated by competition for shared, but limiting, cellular factors, because overexpression of PS in transfected cells does not increase the overall level of PS fragments and replaces endogenous PS (8).PS plays an important role in the generation of amyloid ␤ peptides (A␤) by facilitating intramembranous ␥-cleavage of ␤-amyloid protein precursor (␤APP), as evidenced by the lack of A␤ production and accumulation of ␤APP C-terminal stubs in cells established from PS-null mice (9 -11). In contrast, FADlinked mutations in PS increase the production of highly fibrillogenic A␤42 (12-15), which is the initial and predominantly deposited A␤ species in AD brains (16, 17) and normally consists of only ϳ10% of total secreted A␤ (18). Moreover, genetic studies in invertebrates and PS-null mice suggested that ␥-cleavage-like proteolytic cleavage at site 3 to release Notch intracellular domain (NICD), which is the prerequisite for Notch signaling (reviewed in Ref. 19), also is facilitated by PS. Furthermore, recent findings that the two intramembranous aspartates within the 6th and 7th transmembrane (TM) domains of PS are required for ␥-secretase activities (20) and that transition state analogue ␥-secretase inhibitors specifically label PS fragments (21-24) strongly support the notion that the PS-containing macroprotein complex catalyzes ␥-cleavage and that PS may represent the catalytic ...

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A Myristoylated Calcium-binding Protein that Preferentially Interacts with the Alzheimer's Disease Presenilin 2 Protein

Cited by 129 publications

References 81 publications

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

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

EDD, the Human Hyperplastic Discs Protein, Has a Role in Progesterone Receptor Coactivation and Potential Involvement in DNA Damage Response

Molecular Cloning and Characterization of CALP/KChIP4, a Novel EF-hand Protein Interacting with Presenilin 2 and Voltage-gated Potassium Channel Subunit Kv4

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A Myristoylated Calcium-binding Protein that Preferentially Interacts with the Alzheimer's Disease Presenilin 2 Protein

Cited by 129 publications

References 81 publications

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

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

EDD, the Human Hyperplastic Discs Protein, Has a Role in Progesterone Receptor Coactivation and Potential Involvement in DNA Damage Response

Molecular Cloning and Characterization of CALP/KChIP4, a Novel EF-hand Protein Interacting with Presenilin 2 and Voltage-gated Potassium Channel Subunit Kv4

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

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