Emerging Roles for SSeCKS/Gravin/AKAP12 in the Control of Cell Proliferation, Cancer Malignancy, and Barriergenesis

Gelman, Irwin H.

doi:10.1177/1947601910392984

Cited by 90 publications

(100 citation statements)

References 104 publications

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“…To identify which AKAP may be responsible for the effects of st-HT31, we studied the effect of CSE and st-Ht31 on the expression of AKAP9 and AKAP12, which maintain endothelial barrier function and the blood-retinal barrier, respectively (8,35). In addition, AKAP12 regulates E-cadherin expression in prostate epithelial cells (1), and AKAP5 interacts with cadherins (10).…”

Section: Disruption Of Akap Complexes Prevents Cse-induced Loss Of Akmentioning

confidence: 99%

A-kinase anchoring proteins contribute to loss of E-cadherin and bronchial epithelial barrier by cigarette smoke

Oldenburger

Poppinga

Kos

et al. 2014

American Journal of Physiology-Cell Physiology

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Airway epithelium, which forms the first barrier towards environmental insults, is disturbed by cigarette smoking, a major risk factor for developing chronic obstructive pulmonary disease (COPD). A-kinase anchoring proteins (AKAP) maintain endothelial barrier function and coordinate subcellular localization of protein kinase A (PKA). However, the role of AKAPs in epithelial barrier function is unknown. We studied the role of AKAPs in regulating human bronchial epithelial (Hogg JC, Timens W. Annu Rev Pathol 4: 435-459, 2009; HBE) barrier. Cigarette smoke extract (CSE) reduced barrier function in 16HBE cells and the expression of the adhesion molecule E-cadherin specifically at the cell membrane. In addition, CSE reduced the protein expression of the AKAP family member AKAP9 at the cell membrane. The expression of AKAP5 and AKAP12 was unaffected by CSE. AKAP9 interacted and colocalized with E-cadherin at the cell membrane, suggesting that the reduction of both proteins may be related. Interestingly, disruption of AKAP-PKA interactions by st-Ht31 prevented the CSE-induced reduction of Ecadherin and AKAP9 protein expression and subsequent loss of barrier function. Silencing of AKAP9 reduced the functional epithelial barrier and prevented the ability of st-Ht31 to restore membrane localization of E-cadherin. Our data suggest the possibility of a specific role for AKAP9 in the maintenance of the epithelial barrier. E-cadherin, but not AKAP9, protein expression was reduced in lung tissue from COPD patients compared with controls. However, AKAP9 mRNA expression was decreased in primary bronchial epithelial cells from current smokers compared with non/ex-smokers. In conclusion, our results indicate that AKAP proteins, most likely AKAP9, maintain the bronchial epithelial barrier by regulating the E-cadherin expression at the cell membrane.

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Section: Disruption Of Akap Complexes Prevents Cse-induced Loss Of Akmentioning

confidence: 99%

A-kinase anchoring proteins contribute to loss of E-cadherin and bronchial epithelial barrier by cigarette smoke

Oldenburger

Poppinga

Kos

et al. 2014

American Journal of Physiology-Cell Physiology

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“…Further confounding the issue, PKC␣ promotes proliferation of androgen receptor-negative PC-3 CaP cells, whereas it along with PKC␦ promotes apoptosis (17) in the androgen-responsive cell line LNCaP (18 -22). Our laboratory identified SSeCKS (for Src-suppressed C kinase substrate) as a substrate of PKC whose expression is severely downregulated in src-and ras-transformed cells (23,24). Subsequently, Jaken and co-workers (25,26) identified STICK72, which encodes a "Ͼ200-kDa" PKC substrate with PS binding activity, as identical to SSeCKS.…”

mentioning

confidence: 99%

“…SSeCKS has many similarities to the well studied PKC substrate MARCKS, although they have quite different sequences and molecular weights. These include transcriptional suppression by v-src, PS-induced binding to PKC, N-terminal myristoylation, a predicted rodlike shape, heat stability, severely retarded mobility on SDS-PAGE, Ca 2ϩ -dependent calmodulin binding, and PMA-induced translocation to perinuclear sites (24,27). We recently showed that SSeCKS can associate with PKC␣, -␦, and -⑀ isozymes when overexpressed (28).…”

mentioning

confidence: 99%

Control of Protein Kinase C Activity, Phorbol Ester-induced Cytoskeletal Remodeling, and Cell Survival Signals by the Scaffolding Protein SSeCKS/GRAVIN/AKAP12

Guo¹,

Gao

Rothschild

et al. 2011

Journal of Biological Chemistry

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Background: SSeCKS/GRAVIN/AKAP12 is a major protein kinase C substrate and binding protein.Results: SSeCKS binding of PKC via two homologous domains is required for attenuation of PKC activity and transduction of phorbol ester-induced cytoskeletal remodeling and survival signals. Conclusion: SSeCKS controls PKC signaling via direct scaffolding interactions. Significance: PKC signaling is regulated by the spatiotemporal scaffolding activity of SSeCKS.

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“…Aberrant DNA methylation in the promoter region has been shown to specifically silence AKAP12 in Src-and Ras-transformed fibroblasts. 10 Reexpression of AKAP12 in vitro and in vivo suppresses oncogenic growth, 21 while overexpression of AKAP12 leads to cell cycle arrest. 22 In line with this, cells react with increased AKAP12 expression levels upon mitogenic stimuli.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic silencing of AKAP12 in juvenile myelomonocytic leukemia

et al. 2016

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A-kinase anchor protein 12 (AKAP12) is a regulator of protein kinase A and protein kinase C signaling, acting downstream of RAS. Epigenetic silencing of AKAP12 has been demonstrated in different cancer entities and this has been linked to the process of tumorigenesis. Here, we used quantitative highresolution DNA methylation measurement by MassARRAY to investigate epigenetic regulation of all three AKAP12 promoters (i.e., a, b, and g) within a large cohort of juvenile myelomonocytic leukemia (JMML) patient samples. The AKAP12a promoter shows DNA hypermethylation in JMML samples, which is associated with decreased AKAP12a expression. Promoter methylation of AKAP12a correlates with older age at diagnosis, elevated levels of fetal hemoglobin and poor prognosis. In silico screening for transcription factor binding motifs around the sites of most pronounced methylation changes in the AKAP12a promoter revealed highly significant scores for GATA-2/-1 sequence motifs. Both transcription factors are known to be involved in the haematopoietic differentiation process. Methylation of a reporter construct containing this region resulted in strong suppression of AKAP12 promoter activity, suggesting that DNA methylation might be involved in the aberrant silencing of the AKAP12 promoter in JMML. Exposure to DNMT-and HDAC-inhibitors reactivates AKAP12a expression in vitro, which could potentially be a mechanism underlying clinical treatment responses upon demethylating therapy. Together, these data provide evidence for epigenetic silencing of AKAP12a in JMML and further emphasize the importance of dysregulated RAS signaling in JMML pathogenesis.

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Emerging Roles for SSeCKS/Gravin/AKAP12 in the Control of Cell Proliferation, Cancer Malignancy, and Barriergenesis

Cited by 90 publications

References 104 publications

A-kinase anchoring proteins contribute to loss of E-cadherin and bronchial epithelial barrier by cigarette smoke

A-kinase anchoring proteins contribute to loss of E-cadherin and bronchial epithelial barrier by cigarette smoke

Control of Protein Kinase C Activity, Phorbol Ester-induced Cytoskeletal Remodeling, and Cell Survival Signals by the Scaffolding Protein SSeCKS/GRAVIN/AKAP12

Epigenetic silencing of AKAP12 in juvenile myelomonocytic leukemia

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