High expression of a cytokeratin-associated protein in many cancers

Egland, Kristi A.; Liu, Xiu Fen; Squires, Stephen; Nagata, Satoshi; Man, Yan‐gao; Bera, Tapan K.; Onda, Masanori; Vincent, James J.; Strausberg, Robert L.; Lee, Byung Kook; Pastan, Ira

doi:10.1073/pnas.0601296103

Cited by 25 publications

(35 citation statements)

References 16 publications

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“…It was recently shown that a BK channel auxiliary protein (LRRC26) is responsible for the hyperpolarized activation of the BK channels in these prostate cancer cells (Yan and Aldrich, 2010). In addition to the prostate, LRRC26 is also highly expressed in normal salivary glands and at low levels in colon, pancreas, and intestine (Egland et al, 2006). In addition, the LRRC26 protein was found in human parotid exosomes along with TMEM16A and NKCC1, proteins that are primarily, if not exclusively, expressed in acinar cells (Gonzalez-Begne et al, 2009).…”

Section: Resultsmentioning

confidence: 98%

“…However, MTX was not entirely without effect as it produced a 2-fold increase in the speed of parotid BK channel activation. We showed that the limited action of MTX on the voltage dependence of BK channel activation in parotid cells was probably attributed to the existence of a BK channel accessory protein, LRRC26, which is expressed in salivary glands, including parotid (Egland et al, 2006;Gonzalez-Begne et al, 2009). Coexpression of parSlo with LRRC26 produced chan- molpharm.aspetjournals.org nels that mimicked many of the properties of those in the native cells, including 1) a hyperpolarized activation range, 2) resistance to MTX modification of steady-state activation, and 3) a speeding of gating kinetics by MTX.…”

Section: Discussionmentioning

confidence: 99%

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The LRRC26 Protein Selectively Alters the Efficacy of BK Channel Activators

Almássy

Begenisich²

2011

Mol Pharmacol

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Large conductance, Ca 2ϩ -activated K channel proteins are involved in a wide range of physiological activities, so there is considerable interest in the pharmacology of large conductance calcium-activated K (BK) channels. One potent activator of BK channels is mallotoxin (MTX), which produces a very large hyperpolarizing shift of the voltage gating of heterologously expressed BK channels and causes a dramatic increase in the activity of BK channels in human smooth muscle cells. However, we found that MTX shifted the steady-state activation of BK channels in native parotid acinar cells by only 6 mV. This was not because the parotid BK isoform (parSlo) is inherently insensitive to MTX as MTX shifted the activation of heterologously expressed parSlo channels by 70 mV. Even though MTX had a minimal effect on steady-state activation of parotid BK channels, it produced an approximate 2-fold speeding of the channel-gating kinetics. The BK channels in parotid acinar cells have a much more hyperpolarized voltage activation range than BK channels in most other cell types. We found that this is probably attributable to an accessory protein, LRRC26, which is expressed in parotid glands: expressed parSlo ϩ LRRC26 channels were resistant to the actions of MTX. Another class of BK activators is the benzimidazalones that includes 1,3-dihydro-1-(2-hydroxy-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS-1619). Although the LRRC26 accessory protein strongly inhibited the ability of MTX to activate BK channels, we found that it had only a small effect on the action of NS-1619 on BK channels. Thus, the LRRC26 BK channel accessory protein selectively alters the pharmacology of BK channels.

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

The LRRC26 Protein Selectively Alters the Efficacy of BK Channel Activators

Almássy

Begenisich²

2011

Mol Pharmacol

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“…Another possibility is that membrane proteins may bind directly to IFs, which may be the case for polycystin-1 [90], a protein that, in addition to its well-known apical cilium localization, also concentrates around desmosomes [91]. Other examples are the interaction between aquaporin and filensin [92] and a 334-aa cancerassociated protein with the structure of a membrane protein that colocalizes with IFs [93]. It is also conceivable, that IFs may serve as scaffolds for extrinsic membrane proteins that, in turn interact with membrane proteins.…”

Section: Role Of Keratin Ifs In Epithelial Polarizationmentioning

confidence: 99%

Intermediate filaments: A role in epithelial polarity

Oriolo

Wald

Palau

et al. 2007

Experimental Cell Research

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Intermediate filaments have long been considered mechanical components of the cell that provide resistance to deformation stress. Practical experimental problems, including insolubility, lack of good pharmacological antagonists, and the paucity of powerful genetic models, have handicapped the research of other functions. In single-layered epithelial cells, keratin intermediate filaments are cortical, either apically polarized or apico-lateral. This review analyzes phenotypes of genetic manipulations of simple epithelial cell keratins in mice and C. elegans that strongly suggest a role of keratins in apico-basal polarization and membrane traffic. Published evidence that intermediate filaments can act as scaffolds for proteins involved in membrane traffic and signaling is also discussed. Such a scaffolding function would generate a highly polarized compartment within the cytoplasm of simple epithelial cells. While in most cases mechanistic explanations for the keratinnull or overexpression phenotypes are still missing, it is hoped investigators will be encouraged to study these as yet poorly understood functions of intermediate filaments.

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“…Before its recognition as a likely BK regulatory subunit, message and protein for human LRRC26 was initially observed in a variety of cancer cell lines and human cancer samples (CAPC) (16). CAPC was found to inhibit tumor cell proliferation and tumor growth by regulating NF-κB and its target genes (20).…”

Section: Potential Roles Of Lrrc26-containing Bk Channels In Tumor Grmentioning

confidence: 99%

“…LRRC26 was originally identified in several cancer cell lines and termed cytokeratin-associated protein in cancers (CAPC) (16). Subsequently it was shown to be a regulatory subunit of BK channels (12), later defined as γ1 (14).…”

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confidence: 99%

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

Yang

González-Pérez

Mukaibo

et al. 2017

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

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Leucine-rich-repeat-containing protein 26 (LRRC26) is the regulatory γ1 subunit of Ca 2+ -and voltage-dependent BK-type K + channels. BK channels that contain LRRC26 subunits are active near normal resting potentials even without Ca 2+ , suggesting they play unique physiological roles, likely limited to very specific cell types and cellular functions. By using Lrrc26 KO mice with a β-gal reporter, Lrrc26 promoter activity is found in secretory epithelial cells, especially acinar epithelial cells in lacrimal and salivary glands, and also goblet and Paneth cells in intestine and colon, although absent from neurons. We establish the presence of LRRC26 protein in eight secretory tissues or tissues with significant secretory epithelium and show that LRRC26 protein coassembles with the pore-forming BK α-subunit in at least three tissues: lacrimal gland, parotid gland, and colon. In lacrimal, parotid, and submandibular gland acinar cells, LRRC26 KO shifts BK gating to be like α-subunit-only BK channels. Finally, LRRC26 KO mimics the effect of SLO1/BK KO in reducing [K + ] in saliva. LRRC26-containing BK channels are competent to contribute to resting K + efflux at normal cell membrane potentials with resting cytosolic Ca 2+ concentrations and likely play a critical physiological role in supporting normal secretory function in all secretory epithelial cells.L arge-conductance, voltage-and Ca 2+ -regulated BK-type channels are widely expressed proteins, found not only in excitable cells, such as neurons, muscle, and endocrine cells, but also nonexcitable cells, including salivary (1) and lacrimal gland (2) acinar cells, and colonic crypt cells (3). Given the almost ubiquitous expression of BK channels among cells that play quite distinct physiological roles, it is particularly important to define the specific properties of BK channels in a given cell type and determine what the specific physiological role played by BK channels in a given cell may be. A hallmark of BK channels is their dual regulation by both membrane voltage and cytosolic Ca 2+ (4), both properties embedded within the tetramer of pore-forming α-subunits of each BK channel (5). However, the specific range of voltages over which a BK channel is active at a given Ca 2+ concentration is markedly dependent on the identity of regulatory subunits that can coassemble with the α-subunit in the mature channel complex. Of the two families of known BK regulatory subunits, β (6-11) and γ (12-14), an important feature of many of these subunits is the ability to shift the range of activation voltages at a given Ca 2+ . Although there is growing information about the loci of expression and functional roles of BK channels containing specific β-subunits (15), much less is known about those BK channels containing the γ1 (LRRC26, leucine-rich-repeat-containing subunit 26) subunit. However, LRRC26 is particularly fascinating because it causes the largest shift in BK gating (approximately −120 mV) of any known non-pore-forming regulatory subunit, resulting in BK channels that...

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High expression of a cytokeratin-associated protein in many cancers

Abstract: We have described previously a cDNA library made from membrane-bound polysomal mRNA prepared from breast and prostate cancer cell lines. The library is highly enriched for cDNAs encoding membrane proteins, secreted proteins, and cytokeratins.

Cited by 25 publications

References 16 publications

The LRRC26 Protein Selectively Alters the Efficacy of BK Channel Activators

The LRRC26 Protein Selectively Alters the Efficacy of BK Channel Activators

Intermediate filaments: A role in epithelial polarity

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

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