Disease relevance of CIB1

• NBR1 interacts with fasciculation and elongation protein zeta-1 (FEZ1) and calcium and integrin binding protein (CIB) and shows developmentally restricted expression in the neural tube [1].
• CONCLUSION: The CI regimen was virtually identical to CIB with regard to response rate, PFS, survival, and toxicity profile [2].
• Downregulation of the KIP family members p27(KIP1) and p57(KIP2) by SKP2 and the role of methylation in p57(KIP2) inactivation in nonsmall cell lung cancer [3].
• Expression of second class of KIP protein p57KIP2 in human colorectal carcinoma [4].
• The pharmacokinetics of cyclophosphamide (CP) and its cytotoxic metabolite 4-hydroxycyclophosphamide (4-OHCP) have been studied in multiple myeloma patients treated with the CIB (CP, interferon-alpha (IFN-alpha) and betamethasone) regimen [5].

High impact information on CIB1

• CIB1 is an endogenous inhibitor of agonist-induced integrin alphaIIbbeta3 activation [6].
• Conversely, the RNA interference-mediated depletion of CIB1 increases cell migration and reduces normal adhesion-induced PAK1 activation and cofilin phosphorylation [7].
• Essential role of CIB1 in regulating PAK1 activation and cell migration [7].
• We report here the identification of a calcium-binding protein, calmyrin, that interacts preferentially with presenilin 2 (PS2) [8].
• Functionally, calmyrin and PS2 increase cell death when cotransfected into HeLa cells [8].

Chemical compound and disease context of CIB1

• Phase II study of cyclophosphamide, interferon-alpha and betamethasone (CIB) as induction therapy for patients 60-75 years of age with multiple myeloma stages II and III [9].

Biological context of CIB1

• The crystal structure for Ca(2+)-bound CIB1 has been determined at 2.0 A resolution and reveals a compact alpha-helical protein containing four EF-hands, the last two of which bind calcium ions in the standard fashion seen in many other EF-hand proteins [10].
• Differences in structure, oligomeric state, and phylogeny define a new family of CIB1-related proteins that extends from arthropods to humans [10].
• These results allude to several provocative possibilities for a dynamic role of calmyrin in signaling, cell death, and AD [8].
• The collective data in this paper suggest that KIP plays a positive role in telomere length maintenance and/or regulation and may represent a novel target for anti-cancer drug development [11].
• Calmyrin is a myristoylated calcium binding protein that contains four putative EF-hands [12].

Anatomical context of CIB1

• Calmyrin is myristoylated, membrane-associated, and colocalizes with PS2 when the two proteins are overexpressed in HeLa cells [8].
• Calcium-and integrin-binding protein regulates focal adhesion kinase activity during platelet spreading on immobilized fibrinogen [13].
• Using Chinese hamster ovary (CHO) cells as a model, we demonstrate that CIB induces cell migration [13].
• Thus, although protein levels of Calmyrin are low in human forebrain, its cellular localization as well as its altered distribution in AD brain suggest that it may be involved in the pathogenesis of AD [14].
• Calmyrin immunosignals were in part associated with diffuse and senile plaques [14].

Associations of CIB1 with chemical compounds

• In contrast, overexpression of CIB1 or CaBP1 attenuated InsP(3)R-dependent Ca(2+) signaling, and in vitro pre-exposure to CIB1 reduced the number of channels available for subsequent stimulation by InsP(3) [15].
• Glutathione bound in this fashion suggests CIB1 may be redox regulated [16].
• CIB binding to alpha(IIb) cytoplasmic tail peptides, as measured by intrinsic tryptophan fluorescence, indicates a CIB-binding site within a hydrophobic, 15-amino acid, membrane-proximal region of alpha(IIb) [17].
• CIB engineered to contain alanine substitutions in the implicated regions retained wild type secondary structure as determined by circular dichroism, yet failed to bind alpha(IIb) in 11 of 12 cases, whereas CIB mutated within the N terminus retained binding activity [17].
• CIB1 (CIB) is an EF-hand-containing protein that binds multiple effector proteins, including the platelet alphaIIbbeta3 integrin and several serine/threonine kinases and potentially modulates their function [10].

Physical interactions of CIB1

• By yeast two-hybrid assays, we found that both EF-hands 3 and 4 of calmyrin must be intact for calmyrin to interact with PS2-loop sequences [12].
• The Alzheimer disease-related calcium-binding protein Calmyrin is present in human forebrain with an altered distribution in Alzheimer's as compared to normal ageing brains [14].
• The small GTPase Rac3 interacts with the integrin-binding protein CIB and promotes integrin alpha(IIb)beta(3)-mediated adhesion and spreading [18].
• Here we demonstrate that an association between GPIIb/IIIa and calcium- and integrin-binding protein (CIB) is required for the process of platelet spreading [19].
• Molecular basis of CIB binding to the integrin alpha IIb cytoplasmic domain [17].

Co-localisations of CIB1

• Third, immunolocalization experiments demonstrate that KIP is a nuclear protein that co-localizes with hTERT in cells [11].
• Also, CIB co-localized with active Rac3 to the periphery of cells adhering to fibrinogen [18].

Regulatory relationships of CIB1

• Taken together, our results suggest that CIB regulates platelet spreading through the regulation of FAK activation [13].
• Calcium binding sequences in calmyrin regulates interaction with presenilin-2 [12].

Other interactions of CIB1

• Immunoprecipitation analysis indicates that CIB associates with focal adhesion kinase (FAK), a key regulator in focal complex formation, and up-regulates its activity [13].
• Second, antibodies specific to KIP immunoprecipitate human telomerase in cell-free extracts [11].
• Previously, we have shown that, when bound to glycoprotein IIb (GPIIb), calcium- and integrin-binding protein (CIB) regulates platelet spreading on immobilized fibrinogen (Fg) [13].
• Binding of V12Rac3 to CIB was mediated by the C-terminal end of Rac3 and by Rac3 membrane localization [18].
• CIB1 has been implicated in alphaIIb beta3 activation and outside-in signaling through the integrin [20].

Analytical, diagnostic and therapeutic context of CIB1

• Yeast two-hybrid liquid assays, affinity chromatography, and coimmunoprecipitation experiments confirm binding between PS2 and calmyrin [8].
• Immunofluorescence analysis of CIB localization indicates that endogenous CIB accumulates in areas of focal adhesions, and its overexpression up-regulates the formation of focal adhesion complexes compared with control cells [13].
• Using ultraviolet spectroscopy, circular dichroism (CD), and NMR, we found that Ca(2+)-free and -bound calmyrin have substantially different protein conformations [12].
• By site-directed mutagenesis and Ca2+ binding studies, we found that calmyrin binds two Ca2+ ions with a dissociation constant of approximately 53 microM, and that the two C-terminal EF-hands 3 and 4 bind calcium [12].
• Using reverse transcriptase-polymerase chain reaction and Western blot analysis, we detected CIB mRNA and protein ( approximately 25 kDa), respectively, in human platelets [21].

References