Occludin phosphorylation: identification of an occludin kinase in brain and cell extracts as CK2

Smales, Caroline; Ellis, Moira V.; Baumber, Rachel; Hussain, Nayer; Desmond, H.; Staddon, James M.

doi:10.1016/s0014-5793(03)00525-8

Cited by 47 publications

(37 citation statements)

References 25 publications

(35 reference statements)

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“…Similar results have been observed with multiple experimental systems [105,116,120]. Phosphoamino acid analysis of brain extracts [99] as well as endothelial cell [116] and MDCK cell [121] lysates suggest that occludin is primarily phosphorylated on serine and threonine residues and that the slower migrating, hyperphosphorylated form of occludin is associated with phosphorylation on multiple serine residues [121]. Using mass spectrometry of occludin immunoprecipitated from vascular endothelial cells, Sundstrom et al identified five putative occludin phosphosites and in vivo phosphorylation of Ser490 was validated using a phosphospecific antibody (manuscript submitted).…”

Section: Occludin Phosphorylation and Permeabilitysupporting

confidence: 88%

“…The proximal C-terminus includes amino acids 266-412 but has not been formally associated with a domain or conserved functional motif. The proximal region has been shown to be phosphorylated by casein kinase I [97], casein kinase II [97][98][99] and by protein kinase C [100]. Unfortunately, these phosphorylation sites have not been confirmed in vivo.…”

Section: Occludin and Tricellulinmentioning

confidence: 99%

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Vascular permeability in ocular disease and the role of tight junctions

2007

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Vascular permeability is closely linked with angiogenesis in a number of pathologies. In the retina, the normally well-developed blood-retinal barrier is altered in a host of eye diseases preceding or commensurate with angiogenesis. This review examines the literature regarding the tight junction complex that establishes the blood-retinal barrier focusing on the transmembrane proteins occludin and the claudin family and the membrane associated protein zonula occludens. The changes observed in these proteins associated with vascular and epithelial permeability is discussed. Finally, novel literature addressing the link between the tight junction complex and angiogenesis is considered.

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Section: Occludin Phosphorylation and Permeabilitysupporting

confidence: 88%

Section: Occludin and Tricellulinmentioning

confidence: 99%

Vascular permeability in ocular disease and the role of tight junctions

2007

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“…Casein kinase 2 (CK2) phosphorylated OCC at T375 and S379, 41 and in vitro studies pointed to CK2 as OCC kinase. 42 However, the paucity of the phosphorylation sites by PKC contrasted with the multiple phosphorylation residues found in previous reports 8 suggesting the involvement of other kinases in this process. In addition, OCC could be phosphorylated on tyrosine residues by src-like tyrosine kinase, c-Yes.…”

Section: Discussionmentioning

confidence: 79%

Phosphorylation of Claudin-5 and Occludin by Rho Kinase in Brain Endothelial Cells

Yamamoto

Ramirez

Sato

et al. 2008

The American Journal of Pathology

204

147

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Critical to the proper maintenance of blood-brainbarrier (BBB) integrity are the endothelial tight junctions (TJs). Posttranslational modifications of essential endothelial TJ proteins, occludin and claudin-5, contribute and possibly disrupt BBB integrity. Our previous work has shown that Rho kinase (RhoK) activation mediates occludin and claudin-5 phosphorylation resulting in diminished barrier tightness and enhanced monocyte migration across BBB in the setting of human immunodeficiency virus-1 encephalitis (HIVE). To determine whether RhoK can directly phosphorylate TJ proteins, we examined phosphorylation of cytoplasmic domains of recombinant claudin-5 and occludin by RhoK. We found that RhoK predominately phosphorylated two sites on occludin (T382 and S507) and one site on claudin-5 (T207). The blood-brain-barrier (BBB) is composed of specialized nonfenestrated brain microvascular endothelial cells (BMVECs) connected by tight junctions (TJs) in an impermeable monolayer devoid of transcellular pores.1 TJs are composed of claudins and occludin (OCC, integral membrane proteins) and intracellular proteins, zonula occludens (ZO-1 to ZO-3).2 OCC (65-kDa protein) is highly expressed in BMVECs, and it is consistently found along the cell borders of brain endothelium.3,4 OCC is composed of four transmembranous domains with the carboxyl and amino terminals oriented to the cytoplasm and two extracellular loops (44 amino acids and 45 amino acids) spanning the intercellular cleft.5 OCC content is much lower in endothelial cells outside of the central nervous system 6,7 suggesting its active role in BBB function. The phosphorylation state of OCC regulates its association with the cell membrane and barrier permeability, and multiple phosphorylation sites have been identified on OCC serine and threonine residues.8 -10 The cytoplasmic C-terminal domain provides the connection of OCC with the cytoskeleton via accessory proteins, ZO-1 and ZO-2. 11Up to 24 claudins (20-to 24-kDa proteins) sharing the high sequence homology in the first and fourth transmembranous domains and extracellular loops have been identified in mammals.12 Contiguous staining for claudins is found along endothelial cell borders in and outside the central nervous system. BMVECs express predominantly claudin-3 and -5 (CLD5).3,13 The homophilic and heterophilic interactions between the extracellular loops of clauSupported in part by the National Institutes of Health (research grants P01 NS043985, R01 AA015913, and R01 MH65151 to Y.P.; R01 MH072539 to T.I.; and National Center for Research Resources P20RR15635 to T.I. and R.L.C.).M.Y. and S.H.R. contributed equally in this study.

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“…and IV.C.3, we provide a summary and critical discussion on the role of several protein kinases on Sertoli cell BTB function and how these kinases regulate BTB restructuring during the seminiferous epithelial cycle in concert with cytokines, actin regulators, and steroids. However, it must be noted that several other nonreceptor protein kinases [e.g., CK1 (casein kinase 1) and CK2, which are also found at the BTB associating with the N-cadherin/␤-catenin complex but not with nectin/afadin ] (Cordenonsi et al, 1997(Cordenonsi et al, , 1999Smales et al, 2003;Dörfel et al, 2009) and GTPases (e.g., Rho kinase) (Yamamoto et al, 2008), can also regulate the phosphorylation status of occludin, tricellulin, or claudin-5 and adhesion in other epithelia and blood-tissue barriers (e.g., the blood-brain barrier).…”

Section: Nonreceptor Protein Kinases: Focal Adhesionmentioning

confidence: 99%